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JAK2 seems to be a typical cooperating mutation in therapy-related t(8;21)/ AML1-ETO-positive AML

The somatic V617F point mutation, which activates the hematopoietic growth factor receptor-associated JAK2 tyrosine kinase, not only shows a high incidence in the BCR-ABL-negative chronic myeloproliferative disorders but also occurs in lower frequencies in other myeloid malignancies such as myelodysplastic syndrome (MDS) (in around 5% of all cases) or acute myeloid leukemia (AML) with overall incidences between 0.5 and 8% of all cases.1, 2, 3 The distribution of the JAK2 mutations in the diverse cytogenetic and molecular subgroups of AML is not yet clarified. In the study of Lee et al.,1 JAK2 mutations were found in only 3/113 patients leading to an incidence of 2.7%. They were represented in two of three cases by the classical V617F mutation, in one case by a K607N mutation. Both cases with a V617F were diagnosed as AML with the prognostically favorable reciprocal translocation t(8;21)(q22;q22)/AML1-ETO.1

Based on these findings, we analyzed the JAK2 mutation status in 24 consecutive patients with AML with t(8;21)/AML1-ETO. Of these, 20 cases were diagnosed as untreated de novo AML, three cases showed therapy-associated AML (t-AML) after previous malignancies (two after treatment of breast cancer and one after seminoma) whereas one case had relapse of de novo AML. All cases underwent investigation by cytomorphologic evaluation in accordance with the FAB/WHO classification, cytogenetic analysis, interphase fluorescence in situ hybridization and molecular testing for the AML1-ETO gene fusion and JAK2 mutation as reported before.3 A V617F mutation was found in two of the 24 cases (8%). Interestingly, both mutated cases were therapy-related after chemotherapy including antracyclines (AC: doxorubicin and cyclophosphamide) and topoisomerase inhibitors (PEB: cisplatin, ectoposide, bleomycin), respectively. The first patient was a 72-year-old woman with AML M1 5 years after breast cancer (peripheral leukocytes: 12 G/L; hemoglobin: 6.0 g/dL, thrombocytes: 60 G/L). The second patient was a 40-year-old male with AML M2 6 years after testicular seminoma (peripheral leukocytes: 16.3 G/L; hemoglobin: 8.4 g/dl; thrombocytes: 31 G/L). Thus, two of three cases with t-AML t(8;21)/AML1-ETO were JAK2 mutated in contrast to the 21 de novo patients who were all negative for the JAK2 mutation. These data for the first time suggest that JAK2 may be a typical additional aberration in AML with therapy-related t(8;21)/AML1-ETO after treatment with antracyclines and topoisomerase inhibitors.

According to the two-hit model,4 leukemogenesis in AML needs the cooperation of at least two different types of mutations: class I mutations induce myeloproliferation via activating mutations involving signal transduction pathways, whereas class II mutations are frequently represented by reciprocal gene fusions and lead to a stop of differentiation. The JAK2 mutation mediating increased activity of the JAK/STAT pathway and increased cell proliferation and survival5 is conceived as class I mutation in accordance with this model. The AML1-ETO gene fusion, which is assumed to repress myeloid-specific promoters and suppress the transcriptional activation function of the normal AML1 gene, would represent a class II mutation in this context. In the previous study by Lee et al.,1 it was not annotated whether the two cases with t(8;21)/AML1-ETO were de novo or therapy-related AML. However, these two cases together with our two cases with JAK2 mutated t(8;21)/AML1-ETO AML suggest that the JAK2 mutation cooperates as class I mutation in leukemogenesis with t(8;21)/AML1-ETO as class II mutation and this may be true especially for therapy-related AML. Also in de novo AML with t(8;21)/AML1-ETO class I mutations such as FLT3, KIT or NRAS, mutations were found at relatively high frequencies, whereas they are rarely detected in t-AML.6, 7 Thus, we suggest that the occurrence of JAK2 mutations in t-AML may be more a matter of pathogenesis than of function in a way that in contrast to other class I mutations JAK2 V617F may be inducible by tumor-eliminating agents. Desta et al.8 described two cases of t-MDS/t-AML with the V617F mutation in normal karyotype and myeloproliferative features with splenomegaly. Thus, it should be supposed that the V617F mutation occurs in t-AML also in other cytogenetic subgroups and interacts with other yet unidentified cooperating mutations as well. In contrast to the two normal karyotype cases, both t(8;21) cases of our study did not show any myeloproliferative features with respect to peripheral blood counts and bone marrow morphology and did not present with splenomegaly.

Only the analysis of larger cohorts of de novo AML and t-AML with respect to V617F in distinct cytogenetic and molecular subgroups will specify the interactions of the JAK2 mutation in AML and will reveal insights into its prognostic impact and into its relationship with previous chemo- or radiotherapy.


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Correspondence to S Schnittger.

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Schnittger, S., Bacher, U., Kern, W. et al. JAK2 seems to be a typical cooperating mutation in therapy-related t(8;21)/ AML1-ETO-positive AML. Leukemia 21, 183–184 (2007).

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