Mutation analysis of TET2 , IDH1 , IDH2 and ASXL1 in chronic myeloid leukemia

Acquired somatic mutations affecting TET oncogene family number 2 (TET2), isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) and additional sex combs-like 1 (ASXL1) have been recently described in BCR–ABL-negative neoplasm, myeloproliferative neoplasms (MPN), myelodysplastic syndrome (MDS), MDS/MPN and acute myeloid leukemias (AMLs), including transformations of MDS or MPN.1 TET2 mutations are diverse (frameshift, nonsense and missense mutations) and do not cluster in a particular region of the protein. In contrast, mutations affecting IDH1/2 and ASXL1 are found in restricted regions.2, 3 None of these gene alterations are disease-specific and their incidence ranges from rare to 40%.1 Another important observation from recent related studies is that these mutations can coexist with other pathogenetically relevant mutations including JAK2V617F, sometimes before or emerging in a subclone.4 Therefore, and especially in view of the occurrence of these mutations across varying molecular profiles, their contribution to disease initiation, clonal evolution or blastic transformation is not clear. Also, the possibility of independently emerging multiple abnormal clones rather than monoclonal myeloproliferation is raised. In chronic myeloid leukemia (CML), BCR–ABL fusion is known to be the driver mutation. However, leukemogenesis is a complex process, and genomic heterogeneity of the chronic phase (CP) of the disease has been reported.5 This intrinsic heterogeneity at the molecular level could support a causative link with the varying response to treatment and disease progression. Furthermore, we still do not know for sure whether the BCR–ABL fusion is really the initiating lesion. In order to describe TET2, IDH1, IDH2 and ASXL1 mutation prevalence, to investigate whether these defects could represent an important event in CML initiation, and to define the relationships between acquisition of these mutations and CML transformation and/or imatinib (IM) resistance, here we report on a mutation analysis done on paired samples from CML at diagnosis (untreated), time of IM response and, when available, complete cytogenetic response (CCR) in 91 CML patients treated with IM as first line—most of them from the French SPIRIT trial—and presenting five profiles of IM response at the time of analysis: (1) 25 had CCR and major molecular response (MMR) at 12 months of IM; (2) 11 were in CCR but showed a Ph negative (Ph−) clonal evolution 12–24 months after IM (median 12 months); (3) 20 were in partial cytogenetic response (4 minor and 16 major), 3 of them with additional cytogenetic abnormalities (−Y, +8, +8) 18 months after IM and referred as primary resistant (R1); (4) 20 were in acute transformation (14 myeloid, 6 lymphoid) 4–72 months after onset of IM (median 12 months); and (5) 15 referred as secondary IM-resistant (R2) had relapse in CP (4 molecular relapse, 6 loss of CCR and 5 hematologic relapse). Sokal scores were homogeneously distributed among the five groups except for group 2, which did not have higher scores. Except for group 1, BCR–ABL residual disease evaluated by RQ-PCR remained high (median value 0.09%, according to the International Scale (IS)).