GATA2 Is Overexpressed in 46% of Patients with AML and Normal Karyotype. The Mutational Pattern FLT3-ITD/GATA2/WT1 Could Define a Group of Patients with Normal Karyotype and AML-M1 Subtype.

The presence of recurrent cytogenetic aberrations in AML has diagnostic and prognostic value; however, more than 40% of patients have a normal karyotype. Although the presence of FLT3 mutations, or overexpression (OE) of WT1, EVI1 or BAALC, have been reported to discriminate in this group those with a worse prognosis, more molecular markers are necessary to achieve treatment stratification in this heterogeneous group. The mice homolog of EVI1 (3q26) has been reported to have a role in the HSC proliferation through Gata2 expression, a downstream target gene of the Evi1 oncogene. Therefore, GATA2 (3q21), a transcription factor with a relevant role in hematopoiesis, could be a candidate gene in the leukemogenic transformation of AML. Our aim was to determinate the incidence of GATA2 OE in AML, and its association with other well-defined prognostic factors. We analyzed 7 cell lines and 192 samples of AML patients at diagnosis: 61 were in the favorable prognosis group, 82 in the intermediate (68 with normal karyotype) and 56 in the unfavorable (27 with 3q rearrangements). Expression of GATA2, MDS1/EVI1, EVI1 and WT1 were measured by a RTQ-PCR Taqman assay (Applied Biosystems). Mutations of FLT3 (ITD and D835) were also analyzed. Gene expression arrays were performed with the Human 19K Oligo Array (Center for Applied Genomics, University of New Jersey). We detected a different expression profile among the 3 prognosis groups: 42% and 12% of all AML cases had GATA2 and EVI1 OE respectively, and the frequency increased in the poorer prognosis groups (Table 1). GATA2 OE was detected in 46% of cases with normal karyotype, and was more frequent among samples with FLT3-ITD (68% vs 34%; p=0.0021). Among AML-M1 cases, the number of samples with FLT3-ITD and GATA2 OE was twice than in samples without FLT3 mutations (78% vs 39%). All patients with AML-M1, FLT3-ITD and GATA2 OE had WT1 OE. Gene expression array technology was performed to compare 3 groups of AML-M1: I) FLT3 no mutated and GATA2 OE; II) FLT3 no mutated and GATA2 no OE; and III) FLT3-ITD and GATA2 OE. Unsupervised analysis clearly classified these 3 groups, suggesting they could be prognostically relevant AML subgroups, and allowing the detection of 38 candidate genes that were differentially expressed. Our results show that GATA2 OE is a common event in AML cases with normal karyotype (46%). The mutational pattern FLT3-ITD/GATA2/WT1 could define a subgroup of patients with normal karyotype and AML-M1, with a different expression pattern.