A recent paper by Dastugue et al1 reported the cytogenetic profile of 53 patients with acute megakaryoblastic leukemia (FAB-M7). The authors studied 30 children and 23 adults evaluated by the Groupe Français de Cytogénétique Hématologique, and identified 9 different groups based on their conventional cytogenetic analysis. These groups reflect, in part, the known association of M7 leukemia with Down syndrome, with the t(1;22) translocation, 3q21 or q26 translocations, and with the Philadelphia chromosome [t(9;22)]. No new recurrent abnormalities were identified, although mapping of breakpoints identified possible rearrangement hot spots involving 17q, 11q, 21q, and 16q. Table 1 in their manuscript showed 7 patients with trisomy 19, 1 patient with a hyperdiploid karyotype and an extra copy of chromosome 19, 1 patient with loss of 19, 1 patient with add(19)(p13), and 1 patient with a t(4;19) (p12;?) translocation.

In 2001, we reported the frequent gain of chromosome 19 in megakaryoblastic leukemias using comparative genomic hybridization (CGH).2 We used CGH and G banding to analyze both primary patient samples and megakaryoblastic cell lines, and we found chromosome 19 abnormalities in 4 patients by CGH that we could not identify by G banding. Four of 12 patient samples analyzed demonstrated trisomy 19 (+19q13), with 2 of 4 acute megakaryoblastic leukemia–M7s (AML-M7s) and 2 of 8 secondary acute leukemias, which occurred after a myeloproliferative disorder, demonstrating this abnormality. In addition, 9 of the 11 megakaryocytic leukemia cell lines that we analyzed showed gain of 19 or +19q by CGH.

The larger study by Dastugue et al identified an approximately 20% incidence of chromosome 19 abnormalities with trisomy 19 occurring in 8 (16%) of 50 patients lacking the Philadelphia chromosome. The presence of this abnormality in 8 of 9 cytogenetic subgroups suggests its commonality in this disease process. Little emphasis was placed on this finding in their discussion and our studies suggest that the true incidence of trisomy (or amplification) of chromosome 19 could be even higher, if more sensitive studies such as comparative genomic hybridization or spectral karyotyping (SKY) are performed. This may be especially true in the adult group, as 6 (26%) of 23 adult patients had marker chromosomes, which could contain chromosome19 material, as we found to be the case in the M7 cell lines that we analyzed.

The 19q13 region is gene rich and includes the AKT2, cyclin E, and MLL2 genes, among others. These particular candidate genes have been implicated in solid tumors and are under investigation in hematologic malignancies as well. We believe the Dastugue study provides further support for investigating the role of chromosome 19 abnormalities in the megakaryoblastic leukemias.

In response to our study on the cytogenetic profile of M7, Dr Nimer et al remarked that we have not stressed the frequent gain of chromosome 19 found in our series. Because our study was mainly based on the search of primary changes, and because the numeric abnormalities observed in acute myeloblastic leukemia (AML) are usually regarded as secondary changes, we have not focused our study on the numeric abnormalities. Furthermore, trisomy 19 was not found as an only (ie, a primary) change in our series. However, abnormalities occurring during clonal evolution might also be disease specific and help to characterize the cytogenetic profile of a specific malignancy.

To compare the frequencies of trisomy 19 in M7 and in other AMLs, we have first estimated the relative frequencies of recurrent trisomies in 2 other large series (N.D., unpublished data, 1987-2002). One series is composed of de novo AMLs (n = 1045 cases) and another series includes only AMLs with complex karyotypes (200 AMLs with at least 3 unrelated abnormalities) where M7 represented 1% and 2% of cases, respectively, in these 2 series. In agreement with a previous large study on AML,1-1 trisomy 8 (9.5%) was the most frequent trisomy in the de novo AML series, whereas the other trisomies were much less frequent: trisomy 21 (2.5%), trisomy 4 (2.5%), trisomy 11 (2%), and trisomy 19 (1%). In the complex karyotype series, higher frequencies of trisomies were found, but trisomy 8 remained predominant: trisomy 8 (31%), trisomy 21 (10.5%), trisomy 19 (9%), trisomy 11 (8%), and trisomy 4 (3%). Trisomy 19 was the third most frequent gain. These data are in line with the frequent occurrence of chromosome gains during clonal evolution, and chromosome 19, like chromosomes 8, 21, 11, and 4, is involved in this progression.

A comparison of the above-mentioned frequencies with those reported in our M7 series shows that, unlike in other AMLs, trisomy 8 was not predominant in M7 and that trisomies of chromosomes 19 and 21 were the most frequent gains. Our estimations, based on conventional cytogenetic analyses, are therefore in agreement with a nonrandom gain of chromosomes 19 and 21 in M7. Furthermore, as shown in Alvarez's study,1-2 the frequency of these numeric changes is probably underestimated when only conventional cytogenetics is used. We thus agree with Dr Nimer et al that trisomy 19 also belongs to the spectrum of nonrandom abnormalities characterizing the megakaryoblastic proliferations.

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