Mutations of TET2, IDH1, IDH2 and ASXL1 In Chronic Myeloid Leukemia.

Abstract 3377

It is generally accepted that the BCR-ABL oncoprotein transformes haematopoietic stem cell and initiates chronic myeloid leukemia (CML). However, leukemogenesis is a complex process, and genomic heterogeneity of the chronic phase (CP) of the disease has been reported. At the molecular level, this intrinsic heterogeneity could support a causative link with the varying response to treatment and disease progression. Genetic analysis of candidate genes in myeloid malignancies reported mutations of the ten-eleven translocation 2 (TET2), the isocitrate deshydrogenase (IDH) 1 and IDH2, and the additional sex combs like 1 (ASXL1) genes in myeloproliferative, acute myeloid and myelodysplasic neoplasms. Similarly, we can stipulate that these candidate genes may contribute to phenotypic heterogeneity of CML.

To investigate whether TET2, IDH1, IDH2 and ASXL1 defect could represent a significant event in CML, we selected 91 CML patients (pts) treated with imatinib (IM) at first line and presenting five profiles of IM response at time of the analysis: 1) 25 pts in major molecular response (MMR) at 12 months of IM; 2) 11 pts in CCR but presenting additional Philadelphia (Ph) negative clonal evolution; 3) 20 pts in partial cytogenetic response at 18 months of IM, referred as primary resistant (R1); 4) 20 pts in acute transformation 4 to 72 months after onset IM; and 5) 15 pts relapsing in CP of the disease, referred as secondary resistant (R2). The search for mutation was performed by sequencing the entire TET2 coding region (11 exons), the IDH1 and IDH2 exon 4 and the ASXL1 exon 12.

Analysis of paired samples from CML diagnosis, time of IM response and, when available, CCR revealed: 1) 2 pts (2.2%) in acute transformation presenting 3 TET2 stop mutations not located within conserved region (del at A2079, substitution T4893A - both also been detected at diagnosis -, and del at C4851 which has not been detected at diagnosis, even by mutation-specific ASO-PCR); 2) no IDH1 and IDH2 mutation; and 3) 8 pts (8.7%) presenting ASXl1 stop mutations at diagnosis. Among them, 3 pts (two ins at G646 and one ins at V751) have reached MMR without detected mutations at this time; one R1 pt presenting ins at G646 had major cytogenetic response with 5% Ph+ cells but the mutation was not found at this time and the pt have progressed to MMR 9 months later; one pt with 23 bp del at R634 has evolved in acute transformation with detected mutation at this time; and 3 R2 pts presenting either 4 bp del at S895, del at R860 or 2 pb ins at A752 have lost CCR associated with lost of hematologic response in one case. In this later group of 3 pts, except for del at R860, all ASXL1 mutations were found in samples at time of relapse.

We therefore conclude that, contrary to what has been reported in other myeloid malignancies, TET2, IDH1 and IDH2 are not commonly acquired in CML and may not represent a major genetic event in CML transformation. However, ASXL1 alteration seems to be an early event in CML leukemogenesis but does not seem to participate in the disease transformation.