Moreover, for eight patients with mutations in IKZF1 (n ¼ 3), RUNX1 (n ¼ 3), ASXL1 (n ¼ 1), WT1 (n ¼ 2) and IDH1 (n ¼ 2), matched DNA samples from initial diagnosis at chronic phase were available. In none of the chronic phase CML samples were the respective IKZF1 deletions or RUNX1 and ASXL1 mutations detectable, indicating that mutations in IKZF1 and RUNX1 were acquired at the time of transformation to BC-CML, and thus act as driver mutations in these cases. In contrast, WT1 and IDH1 mutations were detected at diagnosis in chronic phase in one case each.With respect to clinical data, associations with survival for RUNX1, ASXL1, IKZF1 and WT1 alterations were investigated. No molecular parameter was significantly associated with outcome, which may be due to the short median survival in BC-CML (n ¼ 34 patients with survival data available; median overall survival: 9.3 months).In conclusion, the aberrant BCR-ABL kinase causes genomic instability of the CML clone by inefficient DNA repair, resulting in chromosomal alterations and molecular aberrations of transcription factors. This study on 12 genes demonstrated for the first time that in 76.9% of the BC-CML patients, molecular mutations are detectable. The high mutation rate of RUNX1 (33.3%), ASXL1 (20.5%) and IKZF1 (17.9%) represented important molecular abnormalities in the progression of CML. In particular, IKZF1 and RUNX1 alterations, both involved in cell differentiation, were identified as important markers of disease progression from chronic phase to BC. Although this is a comprehensive study, further investigations are required to identify additional pathogenetic alterations, as in four cases (10.2%) of our cohort no chromosomal or molecular genetic alterations were observed in addition to t(9;22)(q34;q11).
Conflict of interestCH, S Schnittger, WK, and TH have equity ownership of MLL Munich Leukemia Laboratory. VG, AK, MZ, CE, S Schindela, and SW are employed by MLL Munich Leukemia Laboratory. MCM and AH declare no conflict of interest.
