SINCE CHEMOTHERAPY beginnings 50 years ago by Farber and his colleagues, childhood leukemia treatment has been one of the most dramatic cancer success stories.1 Currently more than 70% of children with acute lymphoblastic leukemia are alive and disease-free at 5 years, probably making it the most successfully treated of the disseminated human cancers. Certain forms of acute childhood leukemia have a 90% probability of cure, yet there is a group that is still very therapy resistant. Concurrently, in recent years, our knowledge of the molecular and cellular biology underlying these pediatric leukemias has significantly increased. We are at the point where we can reasonably answer these questions: What are the reasons for childhood leukemia treatment success compared with other cancers? Why are certain subgroups of patients therapy-resistant while most patients have very therapy-sensitive disease? I believe that our knowledge of the molecular genetic abnormalities will provide the key to understanding the treatment successes and failures in childhood leukemia.

The post World War II era witnessed the availability of chemical agents with potential value for cancer treatment. In the late 1940s, the thinking by investigators such as Sidney Farber, was that agents that antagonize important metabolites, eg, folic acid, could be useful. One such agent, aminopterin, was found to produce temporary remission in children with acute leukemia.1 By the early 1950s, an entirely different group of agents, ACTH and the glucocorticoids, became available and showed responses in childhood acute leukemia.2 It was apparent, even from these early studies with both folic acid antagonists and glucocorticoids, that childhood acute leukemias were among the most responsive of all cancers studied. Despite these responses, these early agents resulted in few cures. As the 1960s, 1970s, and 1980s progressed, other chemical agents, eg, methotrexate, L-asparginase, epipodophylotoxins, vincristine, anthracyclines, oxazaphosphorines, and more recently myeloablative therapy followed by bone marrow transplantation, have become important in childhood acute leukemia treatment success.

Acute Lymphoblastic Leukemia (ALL)

Probably the single most important advance in childhood acute leukemia treatment is the success with chemotherapy, using a combination of agents. While the late 1940s and 1950s were characterized by single agent chemotherapy development, the 1960s were characterized by the beginning of investigation into multiagent chemotherapy by several groups. These groups included the St. Jude Children's Research Hospital, led by Don Pinkel; the Children's Cancer Study Group “A” (the forerunner of the current Childrens Cancer Group); other investigators in Boston; and later the Pediatric Oncology Group and investigators elsewhere. The relatively rapid dissemination of results demonstrated the success of multiagent chemotherapy. This approach quickly became the accepted form of treatment with dramatic improvement in survival. These results are shown in Fig 1.3 Figure 1 demonstrates the change from the slow improvement of outcomes of single agent therapy in the 1950s to a second dramatic shift in the curve beginning in the mid 1960s, largely a result of combination chemotherapy. As shown in the figure, the results are most dramatic in ALL. Induction chemotherapy with vincristine, prednisone, and L-asparginase, followed by postremission therapy with mercaptopurine and methotrexate, quickly became the standard childhood ALL treatment.

Fig. 1.

Five-year relative survival rates for ALL and AML: End Results Group, National Cancer Institute Surveillance, Epidemiology and End Results Program, 1996. (▪: ALL) and (•: AML) represent defined time periods. The “best fit” curve was drawn by the author.

Fig. 1.

Five-year relative survival rates for ALL and AML: End Results Group, National Cancer Institute Surveillance, Epidemiology and End Results Program, 1996. (▪: ALL) and (•: AML) represent defined time periods. The “best fit” curve was drawn by the author.

Close modal

There were at least two additional therapeutic advances responsible for the significant improvement in outcome during the 1970s and 1980s. One important advance was the introduction of presymptomatic therapy for central nervous system leukemia.4 A second advance was the introduction of alternative combinations and timings of chemotherapy combining multiple agents. Multiagent chemotherapy studies, while reported by several groups throughout the world, were particularly well organized by the Berlin-Frankfurt-Munster groups in Germany5 and the CCG, which demonstrated the value of delayed intensification.6 These multiagent, intensive therapy trials have continued to the present; their future probably will be tied to therapies specific for genetically defined patient subgroups.

After a dramatic improvement in the 1960s and 1970s, the survival curve for ALL began to plateau in the 1980s. Does the last point on the curve in Fig 1 indicate new advances? Time will answer this question and will determine whether the newer therapies will improve the outlook in the questionable period, ie, the 1990s and beyond.

Acute Myelocytic Leukemia (AML)

In childhood AML, combination chemotherapy also had a significant effect on outcomes, as illustrated in Fig 1, although the results have not been as dramatic as in ALL. Remission induction significantly improved with the introduction of cytarabine and anthracycline, resulting in successful remission induction in most patients.7,8 The role of postremission continuation chemotherapy in childhood AML remains uncertain, although recent evidence suggests that intensive postremission treatment with chemotherapy alone or in combination with bone marrow transplantation is often curative.9 Recently, intensive postremission therapies have been shown to result in 50% 5-year survival.10 However, as shown in the figure, there is evidence that newer therapies (and more widespread use of intensive therapies, eg, allogeneic transplantation as described in the next section) are very much needed in this group of diseases.

One of the results of the early years of combination chemotherapy was the demonstration that many leukemias quickly develop drug resistance resulting in subsequent relapse. One solution to this problem was the development of more intensive chemotherapy combined with total body irradiation followed by bone marrow transplantation. Studies in the 1970s and early 1980s demonstrated both the feasibility of this approach and the idea that some patients with therapy-resistant leukemia could be cured with combination chemoradiotherapy followed by matched sibling transplantation.11-13 

In childhood AML, chemotherapy results have always been inferior to those in ALL. Thus in AML, allogeneic bone marrow was proposed as a primary form of therapy. Transplantation demonstrated that intensive postremission chemoradiotherapy followed by allogeneic marrow transplantation resulted in a significant number of patients cured of their disease.11-14 In “biologically” randomized trials, which compared allogeneic matched sibling transplantation with intensive chemotherapy in patients in first remission, disease-free survival of transplanted patients was improved over those who received chemotherapy alone.13,14 In children with AML who have a matched sibling donor, allogeneic transplantation continues to be the treatment of choice. Also, in children with AML who relapse from chemotherapy, marrow transplantation provides an opportunity for disease cure. Patients who lack a matched sibling donor are candidates for autologous transplantation. While providing cures in some patients, the role of autologous transplantation in childhood AML is less clear than for allogeneic transplants. There is evidence that autologous transplants do not provide the immunologic graft-versus-leukemia effect of allogeneic transplants15 and that reinfused autologous marrow may contain leukemia cells.16 

Blood and marrow transplantation in childhood ALL has, with several exceptions, generally been confined to patients who relapse from primary therapy. Because of the excellent outcomes of most children with chemotherapy, relapsed patients have been the focus of most studies. Analysis of results from a large number of patients demonstrate that allogeneic sibling transplant gives results that are superior to chemotherapy.17 In contrast, autologous transplantation in children with ALL gave results that are, in most cases, inferior to sibling transplants but provided alternatives to chemotherapy, especially in children who relapse following primary chemotherapy.18,19 In contrast to standard risk ALL, Philadelphia-chromosome positive ALL continues to have a very poor response to chemotherapy. Allogeneic bone marrow transplant is the preferred treatment, with transplant conducted soon after induction chemotherapy.20 

One of the major difficulties with marrow transplant has been the lack of matched sibling donors for most patients. Alternative donor sources of stem cells represent an exciting development in the field of blood and marrow transplant for acute leukemias. The availability of matched unrelated donors or, more recently, matched, unrelated umbilical cord donors are becoming helpful in providing additional children with transplant options. Preliminary results suggest that children with acute leukemia who receive unrelated donor marrow have outcomes that come close to those with matched sibling donors.21 Unrelated umbilical cord blood has an additional advantage over marrow in that it is readily available.22 The development of large umbilical cord blood banks will allow study of additional patients who lack HLA-matched siblings.

CML is an uncommon leukemia in children, representing less than 4% of the total of approximately 2,600 cases of childhood leukemia in the United States. Childhood CML (not to be confused with juvenile myelomonocytic leukemia) is identical to adult CML with the t(9; 22)(q34; q11) translocation and 210-kD BCR-ABL fusion gene product. The fusion gene product differs from the 185-kD BCR-ABL fusion gene product in t(9; 22)(q34; q11) Philadelphia-chromosome positive ALL (see Table 1). Transplantation is frequently curative in this disease: CML results in children are generally superior to those in adults.23 

Table 1.

Cellular Genotype Defines Major Forms of Childhood Leukemia: Leukemias Often Result from the Fusion of Genes Critical for Signal Transduction or Transcription

Molecular Genetic AbnormalityTranslocationBiochemical DefectAssociated FeaturesReference
Chronic myelogenous leukemia 
BCR-ABL fusion (p210) t(9; 22)(q34; q11) Signal transduction Myeloproliferation 36 
B-cell lineage leukemia 
TEL-AML1 fusion t(12; 21) cryptic Transcription Good prognosis 50 
BCR-ABL fusion (p185) t(9; 22)(q34; q11) Signal transduction Poor prognosis 37 
E2A-PBX fusion t(1; 19)(q23; p13) Transcription Pre-B phenotype, poor response to antimetabolites 66 
MLL-AFX1 fusion t(x; 11)(q13; q23) Transcription  67 
MLL-AF4 fusion t(4; 11)(q21; q23) Transcription Mixed lineage, infants, poor prognosis 39, 40, 45 
MLL-ENL fusion t(11; 19)(q23; p13) Transcription Hyperleukocytosis 38 
IGH-MYC fusion t(8; 14)(q24; q32) Transcription FAB L3, extramedullary disease 68 
IGκ-MYC fusion t(2; 8)(p12; q24) Transcription FAB L3, extramedullary disease 68 
IGλ-MYC fusion t(8; 22)(q24; q11) Transcription FAB L3, extramedullary disease 68 
Hyperdiploidy None Unknown Good prognosis 49 
T-cell lineage leukemia 
TAL1 deletion None Transcription Extramedullary disease, CD2+, CD10− 69 
TCRδ-TAL1 fusion t(1; 14)(p32; q11) Transcription Extramedullary disease, CD2+, CD10− 69 
TCRβ-TAL1 fusion t(1; 7)(p32; q35) Transcription Extramedullary disease, CD2+, CD10− 69 
TCRα-MYC fusion t(8; 14)(q24; q11) Transcription Extramedullary disease 70 
TCRδ-RBTN1 fusion t(11; 14)(p15; q11) Transcription Extramedullary disease 71 
TCRδ-RBTN2 fusion t(11; 14)(p13; q11) Transcription Extramedullary disease 71 
TCRδ-HOX11 fusion t(10; 14)(q24; q11) Transcription Extramedullary disease 72 
TCRβ-LCK fusion t(1; 7)(p34; q34) Signal transduction Extramedullary disease 73 
Acute myelogenous leukemia 
AML 1-ETO fusion t(8; 21)(q22; q22) Transcription FAB M2 41 
CBFβ-MYH11 fusion inv(16)(p13; q22) Transcription FAB M4EO 74 
DEK-CAN fusion t(6; 9)(p23; q34) Transcription Basophilia 75 
MLL-AF1p fusion t(1; 11)(p32; q23) Transcription  76 
MLL-AF1q fusion t(1; 11)(q21; q23) Transcription FAB M4-M5, infants 77 
MLL-AF6 fusion t(6; 11)(q27; q23) Transcription  78 
MLL-AF9 fusion t(9; 11)(p22; q23) Transcription FAB M4, M5, infants 79 
MLL-AF10 fusion t(10; 11)(p12; q23) Transcription FAB M5 80 
MLL-AF17 fusion t(11; 17)(q23; q21) Transcription  81 
MLL-CBP fusion t(11; 16)(q23; p13) Transcription FAB M4, M5, infants 82 
MLL-EEN fusion t(11; 19)(q23; p13) Transcription Infants 83 
MLL-ENL fusion, MLL-ELL fusion t(11; 19)(q23; p13) Transcription Myelodysplastic syndrome 38, 84 
MLL-MLL fusion None Transcription FAB M4, M5 85 
MOZ-CBP fusion t(8; 16)(p11; p13) Chromatin acetylation/Transcription FAB M4, M5 86 
NUP98-HOXA9 fusion t(7; 11)(p15; p15) ? Activate HOXA9 FAB M2, M4 87 
NPM-MLF 1 fusion t(3; 5)(q25; q34) Abnormal traffic Myelodysplastic syndrome 88 
PML-RARα fusion t(15; 17)(q22; q21) Retinoic acid response FAB M3, coagulopathy 42 
Molecular Genetic AbnormalityTranslocationBiochemical DefectAssociated FeaturesReference
Chronic myelogenous leukemia 
BCR-ABL fusion (p210) t(9; 22)(q34; q11) Signal transduction Myeloproliferation 36 
B-cell lineage leukemia 
TEL-AML1 fusion t(12; 21) cryptic Transcription Good prognosis 50 
BCR-ABL fusion (p185) t(9; 22)(q34; q11) Signal transduction Poor prognosis 37 
E2A-PBX fusion t(1; 19)(q23; p13) Transcription Pre-B phenotype, poor response to antimetabolites 66 
MLL-AFX1 fusion t(x; 11)(q13; q23) Transcription  67 
MLL-AF4 fusion t(4; 11)(q21; q23) Transcription Mixed lineage, infants, poor prognosis 39, 40, 45 
MLL-ENL fusion t(11; 19)(q23; p13) Transcription Hyperleukocytosis 38 
IGH-MYC fusion t(8; 14)(q24; q32) Transcription FAB L3, extramedullary disease 68 
IGκ-MYC fusion t(2; 8)(p12; q24) Transcription FAB L3, extramedullary disease 68 
IGλ-MYC fusion t(8; 22)(q24; q11) Transcription FAB L3, extramedullary disease 68 
Hyperdiploidy None Unknown Good prognosis 49 
T-cell lineage leukemia 
TAL1 deletion None Transcription Extramedullary disease, CD2+, CD10− 69 
TCRδ-TAL1 fusion t(1; 14)(p32; q11) Transcription Extramedullary disease, CD2+, CD10− 69 
TCRβ-TAL1 fusion t(1; 7)(p32; q35) Transcription Extramedullary disease, CD2+, CD10− 69 
TCRα-MYC fusion t(8; 14)(q24; q11) Transcription Extramedullary disease 70 
TCRδ-RBTN1 fusion t(11; 14)(p15; q11) Transcription Extramedullary disease 71 
TCRδ-RBTN2 fusion t(11; 14)(p13; q11) Transcription Extramedullary disease 71 
TCRδ-HOX11 fusion t(10; 14)(q24; q11) Transcription Extramedullary disease 72 
TCRβ-LCK fusion t(1; 7)(p34; q34) Signal transduction Extramedullary disease 73 
Acute myelogenous leukemia 
AML 1-ETO fusion t(8; 21)(q22; q22) Transcription FAB M2 41 
CBFβ-MYH11 fusion inv(16)(p13; q22) Transcription FAB M4EO 74 
DEK-CAN fusion t(6; 9)(p23; q34) Transcription Basophilia 75 
MLL-AF1p fusion t(1; 11)(p32; q23) Transcription  76 
MLL-AF1q fusion t(1; 11)(q21; q23) Transcription FAB M4-M5, infants 77 
MLL-AF6 fusion t(6; 11)(q27; q23) Transcription  78 
MLL-AF9 fusion t(9; 11)(p22; q23) Transcription FAB M4, M5, infants 79 
MLL-AF10 fusion t(10; 11)(p12; q23) Transcription FAB M5 80 
MLL-AF17 fusion t(11; 17)(q23; q21) Transcription  81 
MLL-CBP fusion t(11; 16)(q23; p13) Transcription FAB M4, M5, infants 82 
MLL-EEN fusion t(11; 19)(q23; p13) Transcription Infants 83 
MLL-ENL fusion, MLL-ELL fusion t(11; 19)(q23; p13) Transcription Myelodysplastic syndrome 38, 84 
MLL-MLL fusion None Transcription FAB M4, M5 85 
MOZ-CBP fusion t(8; 16)(p11; p13) Chromatin acetylation/Transcription FAB M4, M5 86 
NUP98-HOXA9 fusion t(7; 11)(p15; p15) ? Activate HOXA9 FAB M2, M4 87 
NPM-MLF 1 fusion t(3; 5)(q25; q34) Abnormal traffic Myelodysplastic syndrome 88 
PML-RARα fusion t(15; 17)(q22; q21) Retinoic acid response FAB M3, coagulopathy 42 

One of the undesired outcomes following successful treatment of childhood leukemia is the development of late effects; these late effects include the development of second cancers, abnormality of growth, endocrine and cardiac dysfunction, and neuropsychological defects. Second cancers have been found with significant frequency following successful chemotherapy for childhood ALL. One very large CCG study of children followed almost 5 years, demonstrated a seven-fold excess for all cancers and a 22-fold excess for central nervous system (CNS) cancer;24 CNS neoplasms were seen in children who had undergone CNS irradiation and especially in those who were 5 years old or younger at the time of treatment.24 Second neoplasms have also been observed following bone marrow transplantation. One study demonstrated a 6.7-fold increase in second cancers, primarily non-Hodgkin's lymphoma, brain tumors, and melanoma.25 Another study demonstrated an overall incidence of second neoplasms at 9.9% at 13 years posttransplantation.26 

Leukemias sometimes occur following treatment with the epipodophylotoxins, which are topoisomerase II enzyme inhibitors. These leukemias are generally myeloid in type and are the result of a fusion between a portion of the MLL gene (on chromosome 11q23) and one of a variety of other partners. The therapy-related leukemias are included in Table 1. The breakpoints in MLL and the partner genes in these secondary leukemias do not differ from those seen in the primary leukemias involving these same genes.27 

The past 20 years have resulted in an explosion in our knowledge of the phenotypic characteristics of leukemia. In more recent years, knowledge of the phenotype has extended to an understanding of the molecular genetic events that cause cells to become malignant.

As they became available, the application of newer laboratory analyses increased the understanding of acute leukemia biology. Morphologic evaluation over the last 50 years culminated in the widely used French-American-British (FAB) classification of childhood acute leukemia; these analyses demonstrated that approximately 80% of childhood acute leukemias group as ALL, including FAB LI-L3 types, and 20% group as AML, including FAB MO-M7 types.28 Studies in the 1970s and 1980s used antibodies to immunophenotype lymphoid leukemic blasts, which demonstrated that 85% of cases were B lineage, whereas 15% of cases of ALL were found to be of T lineage.29-31 Moreover, these B-cell lineage leukemias were found to have early B-lymphocyte development, before the maturation of surface immunoglobulin and, therefore, termed “B-precursor ALL.” More recent molecular analysis of ALL has demonstrated partial or incomplete rearrangement of both immunoglobulin (B-cell) and T-cell receptor genes in these leukemias; thus, these lineage relationships suggest that ALL results in aberrant phenotypes. In parallel studies in AML, myeloid cellular phenotype identification advanced significantly with monoclonal antibody development.32 The combination of antibody-based immunophenotyping and molecular techniques allow description of a vast array of cellular phenotypes. Mixed lineage phenotypes, including T + B, T + myeloid, T + B + myeloid, or B + monocyte have been observed.

Immunophenotyping studies suggest that malignant transformation sometimes results in both aberrant and unstable cellular phenotypes. A number of studies have demonstrated these unstable phenotypes but perhaps none more dramatically than one in which leukemia cells with a mature T-lymphocyte phenotype (and irreversible T-cell DNA rearrangements) changed to mature granulocytes in the appropriate environment.33 Such unstable phenotypes are most likely the result of aberrant gene transcription, which occurs as a result of the leukemogenic process.

Many studies over the past 20 years looked at the role of cellular phenotype in predicting therapy response. The associations generally have not been strong and are clearly less predictive than other biologic characteristics, such as molecular genetic abnormalities or total body leukemia burden.

The past 10 years have been an extremely productive period in understanding the molecular genetic abnormalities in childhood acute leukemia. Rapid advances have permitted analysis of the molecular basis for the abnormalities that cause leukemia cells to differ from their normal lymphoid or myeloid progenitor counterparts. A large number of chromosomal translocations associated with distinct molecular genetic abnormalities have been described in acute leukemia (Table 1, also reviewed in references 31, 34, 42). Occasionally, these abnormalities are a consequence of mistakes in the DNA rearrangement of normal lymphoid progenitor cells in the production of functionally diverse immunoglobulin and T-cell receptor molecules. At the time of DNA rearrangement, a cellular proto-oncogene gene, eg, MYC on chromosome 8, may form a fusion gene with the immunoglobulin gene (IGH) enhancer on chromosome 14 in B-lymphoid progenitors resulting in the t(8; 14)(q23; q32.) translocation. The functional outcome of this event is dysregulation of MYC transcription (Table 1, reviewed in ref 36).

In contrast to translocations involving an antigen receptor gene, most pediatric leukemias arise from recombinations that do not involve antigen receptor genes. These rearrangements are the result of breaks and subsequent fusion between portions of the two genes. The final result is a chimeric or fusion gene protein product that in turn produces malignant transformation. These oncogenic fusion proteins most often alter normal cell function through direct dysregulation of signal transduction pathways involved in controlling cellular differentiation and proliferation or, alternatively, transcription of genes critical to these pathways (Table 1). These genetic alterations distinguish the leukemias from solid tumors, which often demonstrate mutations and deletions of “gatekeeper” or “tumor suppressor” genes as opposed to the alteration of “caretaker” or “proto-oncogenes” seen in the pediatric leukemias.

Another interesting aspect of chromosomal translocations of pediatric leukemias is the frequency with which new genes are discovered by DNA breakpoint analysis. A number of new genes that are critical for normal cellular proliferation and differentiation have been discovered through childhood leukemia analysis. Examples of new genes that were discovered through analysis of chromosomal translocations include: the BCR gene in t(9:22) ALL37; the MLL/HRX/ALL-1 gene in t(4; 11) ALL38,39; the AF4/FEL40 genes in t(4; 11) ALL; the AML 1 gene in t(8; 21) AML41; and the PML gene in t(15; 17) acute promyelocytic leukemia.42 

Many cases of childhood ALL do not have detectable chromosomal translocations but instead show hyperdiploidy (with >50 chromosomes) or hypodyloidy. Up to 50% of childhood leukemias do not yet have defined molecular genetic abnormalities. As noted in Table 1, there is a remarkable number of different molecularly defined types of childhood acute leukemias, but much work needs to be done to further define the various molecular genetic events that are critical to development of these leukemias.

It is likely that chemotherapy success with ALL is partially a result of the ability of chemical agents to activate the apoptotic pathways in cells that are “poised to die.” In support of the importance of active programmed cell death, there are a number of studies that demonstrate that agents which are active in the treatment of ALL (eg, corticorsteroids, epipodophylotoxins, anthracyclines) kill cells in part by activation of apoptotic pathways.43 It is tempting to speculate that this killing of cells already poised for death is a very important factor for chemotherapy success in these leukemias. As stated earlier, the most frequent forms of childhood ALL involve cells that are early lymphoid progenitors. Normal cellular counterparts are actively rearranging DNA of the immunoglobulin and T-cell receptor genes in an attempt to produce a useful antigen receptor gene. Successful rearrangement of T-cell or immunoglobulin genes requires precise joining of V-D-J segments; this process has a high propensity for failure. For successful functional antigen-receptor lymphocyte development, these cells must also escape the negative selection processes that delete self-reactive lymphocytes, and finally, these cells must be positively selected by antigen. The entire process results in a very small percentage of lymphoid progenitor cells developing into mature T or B lymphocytes. The process of programmed cell death acts very effectively in preventing the accumulation of cells that have not matured into useful antigen-recognizing T or B lymphocytes.

A second prediction from the hypothesis that ALL arises in cells that are poised to die is that the normal progenitor cells from which these leukemias arise will also be easily killed by the same chemotherapeutic agents. In fact, the lympholytic nature of corticosteroids has long been known; and other potent chemotherapeutic agents, eg, the antimetabolites, have significant effects on the lymphoid system and are often used as immunosuppressive agents.

Radiation, like chemotherapy, induces programmed cell death in both normal progenitor cells and malignant counterparts in leukemia. Radiation therapy is generally used locally, primarily with the CNS and sometimes in treatment of sanctuary sites in childhood acute leukemias.4 Systemic use of irradiation is generally in the context of stem cell replacement from bone marrow or blood. As with the chemotherapeutic agents, cell death induced by radiation is predominately due to apoptosis.

Immune system cytotoxic cells (T lymphocytes and natural killer cells) are important components of childhood acute leukemia treatment with bone marrow/stem cell transplantation (as discussed below). Apoptosis also plays an important role in the immunologic cell death using foreign “killer” cells for therapy.

One of the major challenges in the next several years is continued definition of optimal childhood acute leukemia therapy. Accumulating evidence clearly indicates that molecular genetic characterization will provide the genotypic information to make this possible. A recent group of childhood ALL experts attempted to develop uniform risk criteria based on age, white count, immunophenotype, DNA index, cytogenetics, CNS status, and early response to therapy. Unfortunately, this attempt resulted only in consensus based on age and white count.44 While these features are useful, they lack the needed degree of predictability for the individual patient. An example is the case of infant ALL in which outcomes can be predicted by molecular genetic analysis (the presence or absence of MLL gene rearrangement) much more precisely than with any other feature.45 

It is clear that acute leukemia response to chemotherapy is significantly affected by the presence of certain molecular genetic abnormalities. Some examples of these specific abnormalities and their influence on outcome are included in Table 1. In childhood leukemia, the prognostic importance of molecular genetics is probably most dramatically demonstrated with the abnormalities of the MLL-AF4 and BCR-ABL type. These molecular genetic abnormalities have a profound effect on cell proliferation, maturation, and metabolism. Moreover, these abnormalities define cases that respond extremely poorly to therapy, irrespective of age and other known prognostic features. In these leukemias, it is very likely that the ineffectiveness of chemotherapy in patients with these and other abnormalities is a direct reflection of the biological characteristics of the leukemia cells. The author's bias, shared by others,46 is that the understanding of cellular genotypes will be the most factor in deciding optimal therapy, and that leukemia genotype will soon replace age, white count, immunophenotype, and other surrogate markers for leukemia cell biology.

Studies in the 1980s demonstrated that ALL patients with increased blast cell DNA content had a more favorable response to chemotherapy.47 The increased blast cell DNA is the result of hyperdiploidy (>50 chromosome per cell). Of some interest are the observations that hyperdiploid ALL blasts tend to accumulate higher levels of methotrexate polyglutamates than ALL cells that are not hyperdiploid.48 Increased sensitivity to antimetabolities and other drugs may explain the more favorable response to chemotherapy among children who have hyperdiploid ALL.49 

Recently, the prognostic importance of TEL gene rearrangement as an indicator of the TEL-AML1 fusion gene (associated with a cryptic translocation involving chromosomes 12 and 21) has emerged.50 Excellent prognosis in cases with TEL rearrangement is observed with the use of antimetabolite-based therapy, known to be relatively free of long-term side effects. Of interest will be future studies to determine why TEL-AML1 leukemia is so responsive to antimetabolites. Perhaps these studies will take us, full circle, back to the early work of Farber et al 50 years ago with antimetabolites. Finally, it should be noted that TEL rearrangements are generally not seen in cases with hyperdiploidy and therefore these two prognostic indicators are independent of one another.51 

In addition to studying translocation-generated fusion genes and their encoded protein products for their ability to predict outcome, they are likely to become important as specific therapy targets. We already have one example in which the fusion product is used as a therapy target: the PML-RARα (retinoic acid receptor alpha) in acute promyelocytic leukemia (see Table 1). The fusion of PML (a putative transcription factor) with the retinoic acid receptor (RARα) results in a protein that inhibits differentiation and promotes myeloid precursor cell survival.52 Leukemia treatment with high doses of all trans-retinoic acid results in cellular differentiation and remission induction with reduced morbidity, lower treatment cost, and improved long-term outcome.53 This agent acts by directly binding to the PML-RARα protein and directly converting this molecule from an inhibitor to an activator of myeloid differentiation. Interestingly, this treatment alone is not curative, suggesting that additional genetic abnormalities are likely to be important in the disease.

As information develops as to the function of some of the newly defined genes that are altered in acute leukemia (eg, AML 1, MLL, AF4, AF9, PBX), it is likely that it will be possible to use the products of these genes as therapy targets. This type of specific targeting is likely to have advantages in reduced toxicity, including the ability to reduce the use of currently toxic chemotherapeutic agents.

In the future, additional molecular targeting approaches are likely to become important. One, at the DNA level, is to use specific oligonucleotides to induce DNA triplex formations.54 At the mRNA level, specific inhibition may be indicated by antisense oligonucleotide duplex formation55 or by ribozymes.56 At the protein level, a number of targeted approaches are potentially possible: Fusion gene products are generally leukemia specific and if they are expressed on the cell surface (complexed with MHC gene products), they could be recognized by specific cytotoxic T lymphocytes.57 Competitive antagonists or decoys could be used to inhibit several types of proteins, including antigen receptors58 and activated kinases.59 Many of the newly described fusion genes result in unique protein products that bind to DNA and alter transcription of important genes. These altered fusion genes could potentially be deactivated by a variety of techniques within the cell nucleus. Inhibition of the aberrant DNA binding domains of these leukemia-specific, fusion gene transcription factors may be useful for future therapy.

Advances in childhood acute leukemia have, in the author's opinion, been dramatically aided by the willingness (even eagerness) of parents, children, physicians, nurses, and other health care workers to enroll patients on research studies that attempt to advance knowledge in the field. This degree of cooperation and collaboration among the various groups is almost unique in medical history. Children are treated on organized protocols, which, at a minimum, provide standardized treatments, and, frequently, conduct treatment studies that use randomization between one or more therapies. The cooperative spirit with which parents are willing to participate in these studies is remarkable, as most of United States children with acute leukemia are treated with one of these research protocol studies. The high compliance and cooperative spirit among all parties is remarkable and quite different from that in adult tumors. Is there a cause and effect between participation in clinical trials and better therapy outcome? These two factors could be causally unrelated but it is doubtful. In support of protocol-based treatment, there is one important study that indicates that protocol-treated patients have better outcomes than those treated off protocols using “the doctor knows what's best” therapy.60 

There are probably several reasons for the superior childhood leukemia treatment results when compared with other childhood and adult tumors. The protocol-based approach discussed above is important; however, it is the author's suspicion that bone marrow's vascular nature and leukemia cell biology are the most important reasons for these excellent results. Good treatment responses are probably related to the leukemia's highly vascular nature, resulting in good chemotherapeutic agent penetration and reduction of the likelihood of hypoxia which, in turn, reduces the efficacy of chemotherapy and irradiation.61 Interestingly, the leukemia cells may induce neovascularization.62 This neovascularization may be important in the pathogenesis of the leukemias.

The excellent childhood leukemia results are, undoubtedly, at least in part due to the nature of the malignant cells. As noted earlier, childhood leukemias arise in cells that are poised to die, resulting in a high likelihood of activation of pathways of programmed cell death (apotosis) induced by chemotherapy or radiotherapy. Moreover, leukemia cells that are hyperdiploid (as is the case frequently in ALL) have increased uptake of antimetabolites. What is the role of the frequently occurring fusion genes (and their protein products) in therapy response? The answer is probably specific for the particular leukemia, as some fusion gene leukemias have a poor prognosis (eg, BCR-ABL and MLL-AF4), while others have a good prognosis, eg, those involving TEL,51 and PML-RARA.63 

Prediction of the future is, of course, extremely hazardous and therefore it can only be speculated. Fifty years ago Farber et al used a folic acid antagonist as the first successful form of chemotherapy. It is of note that in these past 50 years we have learned that folic acid antagonists and other antimetabolites that inhibit DNA synthesis produce fewer secondary cancers than agents which directly interact with DNA (such as the topoisomerase II inhibitors and the anthracyclines). Incorporation of this information into planning for newer chemotherapy programs will be important.

An understanding of additional molecular genetic defects is clearly important, as the genetic defects shown in Table 1 are only a part of the story. The leukemia clone's evolution probably requires several genetic “hits” and, in late stages of the disease there are probably multiple genetic abnormalities. Examples of other additional genetic abnormalities in these leukemia cells include deletion of p53, the “cellular gatekeeper”64 or p16 INK4a, an important member of the CdK inhibitor family of genes.65 Rapid progress is underway in this field and will hopefully result in an understanding of the sequential and interdependent nature of the important molecular defects that influence tumor progression, therapy resistance, and prognosis.

Continuation of therapy improvements are likely with a better understanding of the genetic events resulting in leukemia. My expectation is that therapy will be individualized based on leukemia cell genotype. The genotype will be complex but therapy is likely to be based on the unique “leukemia genes,” which are central to the early steps in pathogenesis. These very specific “leukemia genes” are of the type shown in Table 1 and should be the basis of any future leukemia classification. Genotype-specific therapies with less systemic side effects (both early and late) will be important in reducing the currently high morbidity rate and improvement of quality of life. Finally, is prevention possible? As our understanding of environmental etiologic agents develops, the situation is hopeful.

I thank Drs Jim Downing, Don Pinkel, Norma Ramsay, Steve Sallan, and Bill Woods for their willingness to assist with this commentary. However, I should be held responsible for errors of omission or commission. I also apologize for my inability, because of space limitations, to properly credit the large number of physicians, scientists, and health care workers who have contributed to the dramatic progress in understanding childhood leukemia over the last 50 years. Who would have imagined this to be possible?

J.H.K. is a recipient of an Outstanding Investigator Grant Award (CA 49721) from the National Cancer Institute.

Address reprint requests to John H. Kersey, MD, University of Minnesota, Box 806 Mayo, 420 Delaware St SE, Minneapolis, MN 55455.

1
Farber
S
Diamond
LK
Mercer
RD
Sylvester
RF
Wolff
JA
Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-Aminopteroyl-glutamic acid (Aminopterin).
New Engl J Med
238
1948
787
2
Pearson
OH
Eliel
LP
Use of primary adrenocorticotropic hormone (ACTH) and cortisone in lymphomas and leukemias.
JAMA
144
1950
1349
3
End Results Group, the National Cancer Institute Surveillance, Epidemiology and End Results Program, 1996
4
Nesbit
ME
Sather
HN
Robison
LL
Ortega
J
Littman
PS
D'Angio
GJ
Hammond
GD
Presymptomatic central nervous system therapy in previously untreated childhood acute lymphoblastic leukaemia: Comparison of 1800 rad and 2400 rad. A report for Children's Cancer Study Group.
Lancet
1
1981
461
5
Pitter
J
Creutzig
V
Reiter
A
Riehm
H
Schellong
G
Childhood leukemia: Cooperative Berlin-Frankfurt-Munster trials in the Federal Republic of Germany.
J Cancer Res Clin Oncol
116
1990
100
6
Tubergen
DG
Gilchrist
GS
O'Brien
RT
Coccia
PF
Sather
HN
Waskerwitz
MJ
Hammond
GD
Improved outcome with delayed intensification for children with acute lymphoblastic leukemia and intermediate presenting features: A Childrens Cancer Group phase III trial.
J Clin Oncol
11
1993
527
7
Woods
WG
Ruymann
FB
Lampkin
BC
Buckley
JD
Bernstein
ID
Strivastava
AD
Smithson
WA
Benjamin
DR
Feig
SA
Kim
TH
Odom
LF
Wells
RJ
Hammond
GD
The role of timing of high-dose cytosine arabinoside intensification and of maintenance therapy in the treatment of children with acute nonlymphocytic leukemia.
Cancer
66
1990
1106
8
Revindranath
Y
Steuben
CP
Kresche
J
High dose cytarabine for intensification of early therapy of childhood acute myeloid leukemia: A Pediatric Oncology Group Study.
J Clin Oncol
9
1991
572
9
Wells
RJ
Woods
WG
Buckley
JD
Odom
LF
Benjamin
D
Bernstein
I
Betcher
D
Feig
S
Kim
T
Ruymann
F
Smithson
W
Srivastana
A
Tannous
R
Buckley
CM
Whitt
JK
Wolff
L
Lampkin
BC
Treatment of newly diagnosed children and adolescents with acute myeloid leukemia: A Childrens Cancer Group Study.
J Clin Oncol
12
1994
2367
10
Woods
WG
Neudorf
S
Gold
S
Sanders
J
Kobrinsky
N
Barnard
D
DeKwarte
J
Arthur
D
Lange
BJ
Aggressive post remission chemotherapy is better than autologous bone marrow transplantation and allogeneic BMT is superior to both in children with acute myeloid leukemia.
Proc ASCO
15
1996
368
11
Thomas
ED
Fiefer
A
Buckner
CD
Storb
R
Current statue of bone marrow transplantation for aplastic anemia and acute leukemia.
Blood
49
1977
671
12
Kersey
JH
Ramsay
NCK
Kim
T
McGlave
P
Krivit
W
Levitt
S
Filipovich
A
Woods
W
O'Leary
M
Coccia
P
Nesbit
MC
Allogeneic bone marrow transplantation in acute non-lymphocytic leukemia.
Blood
60
1982
400
13
Amadori
S
Testi
AM
Arico
M
Comelli
A
Guiliano
M
Madson
E
Masera
G
Rondelli
R
Zanesco
L
Mandelli
F
Prospective comparative study of bone marrow transplantation and post-remission chemotherapy for childhood acute myelogenous leukemia.
J Clin Oncol
11
1993
1046
14
Nesbit
ME Jr
Buckley
JD
Feig
SA
Anderson
JR
Lampkin
B
Bernstein
ID
Kim
TH
Piomelli
S
Kersey
JH
Coccia
PF
O'Reilly
RC
August
C
Thomas
ED
Hammond
GD
Chemotherapy for induction of remission of childhood acute myeloid leukemia followed by marrow transplantation or multi-agent chemotherapy: A report from the Children's Cancer Group.
J Clin Oncol
12
1994
127
15
Horowitz
MM
Gale
RP
Sondel
PM
Goldman
JM
Kersey
J
Kolb
HJ
Rimm
AA
Ringdén
O
Rozman
C
Speck
B
Truitt
RL
Zwaan
FE
Bortin
MM
Graft-versus-leukemia reactions following bone marrow transplantation.
Blood
75
1990
555
16
Brenner
MK
Rill
DR
Moen
RC
Krance
RA
Mirro
J Jr
Anderson
WF
Ihle
JN
Gene-marking to trace origin of relapse after autologous bone marrow transplantation.
Lancet
341
1993
85
17
Barrett
AJ
Horowitz
MM
Pollack
BH
Zhang
MJ
Bortin
MM
Buchanan
GR
Camitta
BM
Ochs
J
Graham-Pole
J
Rowlings
RA
Rimm
AA
Klein
JP
Shuster
JJ
Sobocinski
KA
Gale
RP
Bone marrow transplants from HLA-identical siblings as compared with chemotherapy for children with acute lymphoblastic leukemia in a second remission.
New Engl J Med
331
1994
1253
18
Kersey
J
Weisdorf
D
Nesbit
ME
LeBien
TW
Woods
WG
McGlave
PB
Kim
T
Vallera
DA
Goldman
AI
Bostrom
B
Hurd
D
Ramsay
NKC
Comparison of autologous and allogeneic bone marrow transplantation for treatment of high risk refractory acute lymphoblastic leukemia.
New Engl J Med
319
1987
461
19
Billett
AL
Kornmehl
E
Tarbell
NJ
Weinstein
HJ
Gelber
RD
Ritz
J
Sallan
SE
Autologous bone marrow transplantation after a long first remission for children with acute lymphoblastic leukemia.
Blood
81
1993
1651
20
Forman
SJ
O'Donnell
MR
Nademanee
AP
Snyder
DS
Bierman
PJ
Schmidt
GM
Fahey
JL
Stein
AS
Parker
MP
Blume
KG
Bone marrow transplantation for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia.
Blood
70
1987
587
21
Davies
SM
Wagner
JE
Shu
X
Blazar
B
Katsanis
E
Orchard
PJ
Kersey
JH
Dusenberry
KE
Weisdorf
DJ
McGlave
PB
Ramsay
NKC
Unrelated donor bone marrow transplantation for children with acute leukemia.
J Clin Oncol
15
1997
557
22
Wagner
JE
Rosenthal
J
Sweetman
R
Shu
XO
Davies
SM
Ramsay
NK
McGlave
PB
Sender
L
Cairo
MS
Successful transplantation of HLA-matched and HLA-mismatched umbilical cord from unrelated donors: Analysis of engraftment and acute graft-versus-host disease.
Blood
88
1996
795
23
Gamis
AS
Haake
R
McGlave
P
Ramsay
NKC
Unrelated donor bone marrow transplantation for Philadelphia chromosome-positive chronic myelogenous leukemia in children.
J Clin Oncol
11
1993
834
24
Neglia
JP
Meadows
AT
Robison
LL
Kim
TH
Newton
WA
Ruymann
FB
Sather
HN
Hammond
GD
Second neoplasms after acute lymphoblastic leukemia in childhood.
New Engl J Med
325
1991
1330
25
Witherspoon
RP
Fisher
LD
Schoch
G
Martin
P
Sullivan
KM
Sanders
J
Deeg
HJ
Doney
K
Thomas
D
Storb
R
Thomas
ED
Secondary cancers after bone marrow transplantation for leukemia or aplastic anemia.
New Engl J Med
321
1989
784
26
Bhatia
S
Ramsay
NK
Steinbuch
M
Dusenbery
KE
Shapiro
RS
Weisdorf
DJ
Robison
LL
Miller
JS
Neglia
JP
Malignant neoplasms following bone marrow transplantation.
Blood
87
1996
3633
27
Hunger
SP
Tkachuk
DC
Amylon
MD
Link
MP
Carroll
AJ
Wilborn
JL
Willman
CL
Cleary
MJ
HRX involvement in novo and secondary leukemias with diverse 11q23 abnormalities.
Blood
81
1993
3197
28
Bennett
JM
Catovsky
D
Daniel
MT
Flandrin
G
Galton
AG
Gralnick
HR
Sultan
C
French-American-British (FAB) Co-operative Group
The morphologic classification of acute leukemias: Concordance among observers and clinical correlation.
BrJ Haematol
47
1981
553
29
Kersey
JH
Sabad
A
Gajl-Peczalska
K
Hallgren
HM
Yunis
EJ
Nesbit
ME
Acute lymphoblastic leukemia cells with T (thymus-derived) lymphocyte markers.
Science
182
1973
1355
30
Vogler
LB
Crist
WM
Bockman
DE
Pearl
ER
Lewton
AR
Cooper
MD
Pre-B-cell leukemia. A new phenotype of childhood lymphoblastic leukemia.
New Engl J Med
298
1978
872
31
Pui
CH
Childhood leukemias.
New Engl J Med
332
1995
1618
32
Griffin
JD
Ritz
J
Nadler
LM
Schlossman
SF
Expression of myeloid differentiation antigens on normal and malignant myeloid cells.
J Clin Invest
68
1981
932
33
Griesinger
F
Arthur
DC
Brunning
R
Parkin
JL
Ochoa
AC
Miller
WJ
Wilkowski
CW
Greenberg
JM
Hurvitz
C
Kersey
JH
Mature T-lineage leukemia with growth factor induced multilineage differentiation.
J Exp Med
169
1989
1101
34
Drexler
HG
MacLeod
RA
Borkhardt
A
Janssen
JW
Recurrent chromosomal translocations and fusion genes in leukemia-lymphoma cell lines.
Leukemia
9
1995
480
35
Hagemeijer A, Grosveld G: Molecular cytogenetics of leukemia, in Henderson ES, Lister TA, Greaves MF (eds): Leukemia, Sixth Ed. Philadelphia, PA, Saunders, 1996, p 133
36
Rabbitts
TH
Chromosomal translocations in human cancer.
Nature
372
1994
143
37
Suryanarayan
K
Hunger
SP
Kohler
S
Carroll
AJ
Consistent involvement of the bcr gene by 9; 22 breakpoints in pediatric acute leukemias.
Blood
77
1991
324
38
Tkachuk
DC
Kohler
S
Cleary
ML
Involvement of a homolog of Drosophila trithorax by 11q23 chromosomal translocations in acute leukemias.
Cell
71
1992
691
39
Gu
Y
Nakamura
T
Alder
H
Prasad
R
Canaani
O
Cimino
G
Croce
CM
Canaani
E
The t(4; 11) chromosome translocation of human acute leukemias fuses the ALL-1 gene, related to Drosophila trithorax, to the AF-4 gene.
Cell
71
1992
701
40
Morrissey
J
Tkachuk
DC
Milatovich
A
Francke
U
Link
M
Cleary
ML
A serine/proline-rich protein is fused to HRX in t(4; 11) acute leukemias.
Blood
81
1993
1124
41
Erickson
P
Gao
J
Chang
KS
Look
T
Whisenant
E
Raimondi
S
Lasher
R
Trujillo
J
Rowley
J
Drabkin
H
Identification of breakpoints in t(8; 21) acute myelogenous leukemia and isolation of a fusion transcript, AML 1/ETO with similarity to Drosphila segmentation gene, runt.
Blood
80
1992
1825
42
de Th
H
Lavau
C
Marchio
A
Chomienne
C
Degos
L
Dejean
A
The PML-RARα fusion mRNA generated by the t(15; 17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR.
Cell
66
1991
675
43
Heckman
JA
Apoptosis induced by antisense drugs.
Cancer Metast Rev
11
1992
121
44
Smith
M
Arthur
D
Camitta
B
Carroll
AJ
Crist
W
Gaynon
P
Gelber
R
Heerema
N
Korn
EL
Link
M
Murphy
S
Pui
CH
Pullen
J
Reaman
G
Sallan
SE
Sather
H
Shuster
J
Simon
R
Trigg
M
Tubergen
D
Uckun
F
Ungerleider
R
Uniform approach to risk classification and treatment assignment for children with acute lymphoblastic leukemia.
J Clin Oncol
14
1996
18
45
Chen
CS
Sorensen
HB
Domer
PH
Reaman
GH
Korsmeyer
SJ
Heerema
NA
Hammond
GD
Kersey
JH
Molecular rearrangements on chromosome 11q23 predominate in infant acute lymphoblastic leukemia and are associated with specific biologic variable and poor outcome.
Blood
81
1993
2386
46
Pinkel
D
Selecting treatment for children with acute lymphoblastic leukemia.
J Clin Oncol
14
1996
4
47
Look
AT
Roberson
PK
Williams
DL
Rivera
G
Bowman
WP
Pui
CH
Ochs
J
Abromowitch
M
Kalwansky
D
Dahl
GV
Georgia
S
Murphy
SD
Prognostic importance of blast cell DNA content in acute lymphoblastic leukemia.
Blood
65
1985
1079
48
Whitehead
VM
Vuchich
MJ
Lauer
SJ
Mahoney
D
Carroll
AJ
Shuster
JJ
Esseltine
DW
Payment
C
Look
AT
Akabatu
J
Bowen
T
Taylor
LP
Cammita
B
Pullen
DJ
Accumulation of high levels of methotrexate polyglutamates on lymphoblasts from children with hyperliploid (>50-chromosomes) B-lineage acute lymphoblastic leukemia. A Pediatric Oncology Group Study.
Blood
80
1992
1316
49
Kaspers
GJ
Smets
LA
Pieters
R
Van Zantwijk
CH
Van Wering
ER
Veerman
AJP
Favorable prognosis of hyperdiploid common acute lymphoblastic leukemia may be explained by sensitivity to antimetabolites and other drugs: Results of an in vitro study.
Blood
85
1995
751
50
Rubnitz
JE
Shuster
JJ
Land
VJ
Link
MP
Pullen
DJ
Camitta
BM
Pui
C
Downing
JR
Behm
FG
Case-control study suggests a favorable impact of TEL rearrangement in patients with B-lineage acute lymphoblastic leukemia treated with antimetabolite-based therapy: A Pediatric Oncology Group Study.
Blood
89
1997
1143
51
Rubnitz
JE
Pui
C-H
Shurtleff
SA
Raimondi
SC
Evans
WE
Head
DR
Crist
WM
Rivera
GK
Hancock
ML
Boyett
JM
Buijs
A
Grosveld
G
Downing
JR
Behm
FG
TEL gene rearrangement in acute lymphoblastic leukemia: A new genetic marker with prognostic significance.
J Clin Oncol
15
1997
1150
52
Grignani
F
Ferrucci
PF
Testa
U
Talamo
G
Fagioli
M
Alcalay
M
Mencarelli
A
Grignani
F
Peschle
C
Nicolette
I
Pelicci
PG
The acute promeyoctic leukemia-specific PML-RARα fusion protein inhibits differentiation and promotes survival of myeloid precursor cells.
Cell
74
1993
423
53
Tallman
MS
Differentiating therapy in acute myeloid leukemia.
Leukemia
10
1996
1262
54
Duval-Valentin
G
Thuong
NT
Helene
C
Specific inhibition of transcription by triple helix-forming oligonucleotides.
Proc Natl Acad Sci USA
89
1992
504
55
Stein
CA
Cheng
YC
Antisense oligonucleotides as therapeutic agents — is the bullet really magical?
Science
261
1993
1004
56
Shore
SK
Nabissa
PM
Reddy
EP
Ribozyme-mediated cleavage of the BCRABL oncogene transcript: In vitro cleavage of RNA and in vivo loss of P210 protein-kinase activity.
Oncogene
8
1993
3183
57
Chen
W
Peace
DJ
Rovira
DK
Your
SG
Cheever
MA
T-cell immunity to the joining region of p210BCR-ABL protein.
Proc Natl Acad Sci USA
89
1992
1468
58
Renschler
MF
Bhatt
RR
Dower
WJ
Levy
R
Synthetic peptide ligands of antigen bind receptor induce programmed cell death in human B-cell lymphoma.
Proc Natl Acad Sci USA
91
1994
3623
59
Anafi
M
Gazit
A
Zehavi
A
Ben-Neriah
Y
Levitzki
A
Tyrphostin-induced inhibition of p210bcr-abl typosine kinase induces K562 to differentiate.
Blood
82
1993
3524
60
Meadows
AT
Kramer
S
Hepson
R
Lustboden
E
Jarrett
P
Evans
AE
Survival in childhood acute lymphocytic leukemia.
Cancer Invest
1
1983
49
61
Abrams RA: Recent developments in radiotherapy. Curr Opin Oncol 4:1099, 1992 (Review)
62
Perez-Atayde
AR
Sallan
SE
Tedrow
U
Connors
S
Alfred
E
Folkman
J
Spectrum of tumore angiogenesis in the bone marrow of children with acute lymphoblastic leukemia.
Am J Pathol
150
1997
815
63
Fenaux
P
Castaigne
S
Dombret
H
Archimbaud
E
Duarte
M
Morel
P
Lamy
T
Tilly
H
Guerci
A
Maloisel
F
Bordessoule
D
Sadoun
A
Tiberghien
P
Fegueux
N
Daniel
MT
Chomienne
C
Degos
L
All-transretinoic acid followed by intensive chemotherapy gives a high complete remission rate and may prolong remissions in newly diagnosed acute prolmyelocytic leukemia: A pilot study on 26 cases.
Blood
80
1992
2176
64
Levine
AJ
P53, the cellular gatekeeper for growth and division.
Cell
88
1997
323
65
Okuda
T
Shurtleff
SA
Valentine
MD
Raimondi
SC
Head
DR
Look
AJ
Downing
JK
Frequent deletions of p16 INK4a/MTSI and p15 INK4b/MTS2 in pediatric acute lymphoblastic leukemia.
Blood
85
1995
2312
66
Kamps
MP
Murre
C
Sun
X
Baltimore
D
A new homeobox gene contributes the DNA binding domain of the t(1; 19) translocation in pre-B ALL.
Cell
60
1990
547
67
Parry P, Wei Y, Evans G: Cloning and characterization of the t(x; 11) breakpoint from a leukemia cell line identify a new member of the forkhead gene family. Genes, Chromosomes, Cancer 11:79, 1994
68
Croce
CM
Nowell
PC
Molecular basis of human B-cell neoplasia.
Science
65
1985
1
69
Bash
RO
Crist
WM
Shuster
JJ
Link
MP
Amylon
M
Pullen
J
Carroll
AJ
Buchanan
GR
Smith
RG
Baer
R
Clinical features and outcome of T-cell acute lymphoblastic leukemia in childhood with respect to alterations at the TAL1 locus: A Pediatric Oncology Group Study.
Blood
81
1993
2110
70
Lange
BJ
Raimonda
SC
Heerema
N
Nowell
PC
Minowada
J
Steinherz
PE
Arenson
EB
O'Connor
R
Santoli
D
Pediatric leukemia/lymphoma with t(8; 14)(q24; q11).
Leukemia
6
1992
613
71
Boehm
T
Foroni
L
Kaneko
Y
Perutz
MF
Rabbitts
TH
The rhombitin family of cysteine-rich LIM domain oncogenes: Distinct members are involved in translocations to human chromosomes 11p15 and 11p13.
Proc Natl Acad Sci USA
88
1991
4367
72
Dube
ID
Kamel-Reid
S
Yuan
CC
Lu
M
Wu
X
Corpus
G
Raimondi
SC
Crist
WM
Carroll
AJ
Minowada
J
Baker
JB
A novel human homeobox gene lies at the chromosome 10 breakpoint in lymphoid neoplasias with chromosomal translocation t(10; 14).
Blood
78
1991
2996
73
Burnett
RC
Thirman
MJ
Rowley
JD
Diaz
MO
Molecular analysis of the T-cell acute lymphoblastic leukemia-associated t(1; 7)(p34; q34) that fuses LCK and TCRB.
Blood
84
1994
1232
74
Liu
P
Tarle
SA
Hajra
A
Claxton
DF
Marlton
P
Freedman
M
Siciliano
MJ
Collins
FS
Fusion between transcription factor CBF beta/PEBP2 beta and a myosin heavy chain in acute myeloid leukemia.
Science
261
1993
1041
75
Soekarman
D
von Lindern
M
Daemen
S
deJong
B
Fonatsch
C
Heinze
B
Bartram
C
Hagemeijer
A
Grosveld
G
The translocation (6; 9)(p23; q34) shows consistent rearrangement of two genes and defines a myeloproliferation disorder with specific clinical features.
Blood
79
1992
2990
76
Bernard
OA
Mauchauffe
M
Mecucci
C
Van den Berghe
H
Berger
R
A novel gene AF1p, fused to HRX in t(1; 11)(p32; q23) is not related to AF4, AF9, nor EML.
Oncogene
9
1994
1039
77
Tse
W
Zhu
W
Chen
HS
Cohen
A
A novel gene AF1q, fused to MLL in t(1; 11)(q21; q23) is specifically expressed in leukemia and immature hematopoietic cells.
Blood
83
1995
650
78
Prasad
R
Gu
Y
Alder
H
Nakamura
T
Canaani
O
Saito
H
Huebner
K
Gale
RP
Nowell
PC
Kurijyama
K
Miyazaki
Y
Croce
CM
Canaani
E
Cloning of the ALL-1 fusion partner, the AF-6 gene, involved in acute myeloid leukemias with the t(6; 11) chromosome translocation.
Cancer Res
53
1993
5624
79
Nakamura
T
Alder
H
Gu
Y
Prasad
R
Canaani
O
Kamada
N
Gale
RP
Lange
B
Crist
WM
Nowell
PC
Croce
CM
Canaani
E
Genes on chromosomes 4, 9 and 19 involved in 11q23 abnormalities in acute leukemia share sequence homology and/or common motifs.
Proc Natl Acad Sci USA
90
1993
4631
80
Chaplin
T
Bernard
O
Beaverloo
HB
Saha
U
Hagemeijer
A
Berger
R
Young
BD
The t(10; 11) translocation in acute myeloid leukemia (M5) consistently fuses the leucine zipper motif of AF10 onto the HRX gene.
Blood
86
1995
2078
81
Prasad
R
Leshkowitz
D
Gy
Y
Alder
H
Nakamura
T
Saito
H
Huebner
K
Berger
R
Croce
MCM
Canaani
E
Leucine-zipper dimerization motif encoded by AF17 gene fused to ALL-1 (MLL) in acute leukemia.
Proc Natl Acad Sci USA
91
1994
8107
82
Taki
T
Sako
M
Tsuchida
M
Hayashi
Y
The t(11; 16) (q23; p13) translocation in myelodysplastic syndrome fuses the MLL gene to the CBP gene.
Blood
89
1997
3945
83
So
CW
Caldas
C
Liu
MM
Chen
SJ
Huang
QH
Gu
LJ
Sham
MH
Wiedemann
LM
Chan
LC
EEN encodes for a member of a new family of proteins containing an Src homology 3 domain and is the third gene located on chromosome 19p13 that fuses to MLL in human leukemia.
Proc Natl Acad Sci USA
94
1997
2563
84
Shilatifard
A
Lane
WS
Jackson
KW
Conaway
RC
Conaway
JW
An RNA polymerase II elongation factor encoded by the human ELL gene.
Science
271
1996
1873
85
So
CW
Ma
ZG
Price
CM
Dong
S
Chen
SJ
Gu
LJ
So
CK
Wiedemann
LM
Chan
LC
MLL self fusion medicated by Alu repeat homologous recombination and prognosis of AML-M4/M5 subtypes.
Cancer Res
57
1997
117
86
Borrow
J
Stanton
UP Jr
Andersen
M
Becher
R
Behm
FG
Chaganti
RSK
Civin
CI
Disteche
C
Dube
I
Frischauf
AM
Horsman
D
Mitelman
F
Volinia
S
Watmone
AS
Housman
DE
The translocation t(8; 16)(p11; p13) of acute myeloid leukemia fuses a putative acetyltransferase to the CREB-binding protein.
Nature Genet
14
1996
33
87
Nakamura
T
Largaespada
DA
Lee
MP
Johnson
LA
Ohyashili
K
Toyama
K
Chen
SJ
Willman
CL
Chen
IM
Feinberg
AP
Jenkins
NA
Copeland
NG
Shaughnessy
JD Jr
Fusion of the nucleoporin gene NUP98 to HOXA9 by the chromosome translocation t(7; 11)(p15; p15) in human myeloid leukaemia.
Nature Genet
12
1996
154
88
Yoneda-Kato
N
Look
AT
Kirstein
MN
Valentine
MB
Raimondi
SC
Cohen
KJ
Carroll
AJ
Morris
SW
The t(3; 5)(q25.1; q34) of myelodysplastic syndrome and acute myeloid leukemia produces a novel fusion gene, NPM-MLF1.
Oncogene
12
1996
265

Sign in via your Institution