Kinase-associated gene mutation pattern and clinical relevance in 205 patients with core binding factor leukemias
Authors: Y-S Chen, P-P Wang, Y Hu, Y-M Zhu, B Chen, J-Y Huang, J-M Li, X-Q Weng, Y Yu, Y Shen
Journal: Blood Cancer Journal (2016)

Core binding factor (CBF) leukemia represents an individual subgroup of the disease, which accounts for 20% of acute myeloid leukemia (AML), characterized by the special t(8;21)(q22;q22) translocation most in AML-M2 variant (CBFα leukemia) or inv(16) (p13q22)/t(16;16) rearrangement in AML-M4 with eosinophilia (CBFβ leukemia), respectively. 1Chimerical fusion genes AML1-ETO and CBF-MYH11 are formed by these two cytogenetic changes, respectively, which finally lead to the leukemogenesis. 2Generally, CBF leukemias are considered to have favorable treatment outcome and prognosis and most centers regard CBF markers as 'good' cytogenetic factor, with a 5-year overall survival (OS) rate over 50%. 3 However, given using similar treatment strategy, such as '3+7' regimen in induction and high-dose Ara-C in consolidation, the treatment outcome of CBF leukemia in Chinese patients were not as good as reported by western groups. 4Interestingly, the incidence of CBFβ leukemia is even significantly lower than the western countries, as shown in our previous report; in 1185 AML patients, only 18 M4 with eosinophilia patients were identified.The difference of genetic background between Chinese and western population may be the reason, however, until now, evidence remains unavailable. 5n mouse model, stepwise leukemogenesis in AML with t(8;21)/ AML1-ETO is proved by the phenomena that coexpression of C-KIT N822K and AML1-ETO induces the full development of AML, whereas single or C-KIT is not sufficient to lead to the leukemia.Similarly, transgenic mice of CBF-MYH11 only induce a myeloid maturation block. 6Therefore, it could be concluded that additional mutations, especially kinase-associated mutations, providing a second 'hit' 7 may play a crucial role in the evolving of the disease.In this study, we included 205 newly diagnosed AML patients, including 180 patients with CBFα and 25 patients with CBFβ leukemia, to investigate the potential role of additional mutations beyond AML1-ETO and CBF-MYH11 in these diseases.All the patients received standard first-line treatment of DNR (daunorubicin), A (Ara-c(cytarabine))-like regimen.In the consolidation therapy, young patients were treated with high-dose cytarabine-based chemotherapy.Allogenetic stem cell transplantation was not used as first-line treatment in first time to complete remission.This study was approved by the ethnic board of the participating centers.All patients were given informed consent for both treatment and cryopreservation of bone marrow and peripheral blood according to the Declaration of Helsinki.Genomic DNA and total RNA were extracted as previously reported. 8We had screened the mutational status of FLT3-ITD and -TKD, C-KIT, N-RAS, CEPBA, WT1, ASXL1, DNMT3A, NPM1, MLL, IDH2 and TET2 genes by distinct approaches.A chip-based matrixassisted laser desorption/ionization time-of-flight mass spectrometry analysis system (iPLEXTM, Sequenom, San Diego, CA, USA) was used to assess the mutational status of FLT3-TKD, N-RAS, NPM1, IDH1 and IDH2.For mutations of FLT3-ITD, and those in C-KIT, CEPBA, WT1, ASXL1, DNMT3A and TET2 genes, samples were analyzed by whole-gene sequencing.Six MLL-related common fusion genes, including MLL-AF9, MLL-AF10, MLL-AF6, MLL-ELL,