Leukemias expressing either the TEL-AML1 or BCR-ABL fusion transcript reflect two ends of a clinical spectrum. The TEL-AML1 fusion is expressed in at least 20% of children with the most curable form of acute lymphoblastic leukemia (ALL), which peaks in incidence between 2 and 6 years of age. A number of recent backtracking studies in twins and triplets, as well as studies of newborn Guthrie blood spots, indicate that the TEL-AML1 fusion occurs in utero. Subsequent unidentified molecular events in early childhood appear necessary for the clinical development of precursor B-lineage ALL. In contrast, BCR-ABL+ or Philadelphia chromosome–positive (Ph+) chronic myelogenous leukemia (CML) occurs primarily in adults older than 45 years, presenting as a myeloproliferative disorder that eventually transforms into acute leukemia. As with TEL+ ALL, progression to CML blast crisis requires subsequent unknown molecular events. The BCR-ABL gene fusion is also detected in about 4% of childhood B-lineage ALL and 20% of adult ALL. While the outcome of TEL+ ALL is excellent, that of BCR/ABL+ ALL is quite poor.
TEL-AML1 results from a t(12;21(p12,q22) reciprocal translocation and is one of the most recently identified leukemia-associated fusion transcripts. This cryptic rearrangement is detectable by reverse transcriptase–polymerase chain reaction (RT-PCR) or fluorescence in situ hybridization (FISH) but not by standard cytogenetics. The AML1 gene on chromosome 21q encodes the DNA binding alpha 2 subunit of core binding factor (CBFA2); the TEL gene on 12p encodes a member of the ETS family of transcription factors (ETV6).1 In contrast, the Philadelphia chromosome of CML was first identified among mitotic chromosomes in 1960. Recognition of the t(9;22)(q34;q11) reciprocal translocation in banded cytogenetic preparations of CML revolutionized the field. Later, the BCR/ABL fusion transcript and its constitutively activated tyrosine kinase were discovered.2
Despite the differences in TEL/AML1+ and BCR/ABL+ leukemias, similar questions regarding leukemogenesis remain. The papers in this issue of Blood by Morrow and colleagues (page 3890) and by Jiang and colleagues (page 3897) address some of these questions. Morrow et al successfully transduced murine fetal liver hematopoietic progenitor cells (HPCs) with a retroviral vector expressing TEL-AML1 fusion and observed their differentiation in vitro and in vivo. They showed that TEL-AML1 promotes B-lineage, but not myeloid, development in HPCs in vitro. They observed over a 9-month period that leukemia did not develop in lethally irradiated mice that received transplants of TEL+ HPCs, despite persistence of TEL+ B-cell precursors. In separate murine transplantation experiments, the authors found that TEL-AML1 conferred a competitive advantage on reconstitution of B-cell and myeloid progenitors, but not cells of T lineage. Taken together, these results provide the first direct evidence for preleukemic activity of TEL-AML1; they confirm previous experimental observations that TEL-AML1 is necessary but insufficient for leukemogenesis.
In an attempt to shed light on normal and aberrant hematopoiesis, Jiang and colleagues investigated the expression of AHI-1, a gene whose mutant forms may play a role in leukemogenesis as cooperating oncogenes. The authors studied changes in AHI-1 expression through stages of hematopoiesis by separating purified cells from normal murine and human bone marrow, as well as from patients with chronic phase CML, into subsets representing progressive stages of differentiation. They saw AHI-1 expression significantly decrease in normal marrow and CML cell subpopulations as maturation progressed. However, levels of AHI-1 transcripts were much higher in CML cells than in normal bone marrow cells at each stage of equivalent maturation, including cells in G0. The authors found elevated expression of AHI-1 in a number of leukemia cell lines, and in blasts from several patients with Ph+ ALL, but not Ph– acute myeloid leukemia (AML). Taken together, these results provide evidence that AHI-1 expression is important in normal hematopoiesis and appears deregulated in Ph+ leukemias.