Functional features of RUNX1 mutants in acute transformation of chronic myeloid leukemia and their contribution to inducing murine full-blown leukemia.
The BCR-ABL fusion protein generated by t(9;22)(q34;q11) in chronic myeloid leukemia (CML) plays an essential role in the pathogenesis of the myeloproliferative disorder status at the chronic phase of the disease, but progression from the chronic phase to blast crisis (BC) is believed to require additional mutations. To explore the underlying mechanisms for BC, which is characterized by a blockage of blood cell differentiation, we screened several genes crucial to hematopoiesis and identified 10 types of mutations in RUNX1 among 11 of 85 (12.9%) patients with acute transformation of CML. Most of the mutations occurred in the runt homology domain, including H78Q, W79C, R139G, D171G, R174Q, L71fs-ter94, and V91fs-ter94. Further studies indicated that RUNX1 mutants not only exhibited decreased transactivation activity but also had an inhibitory effect on the WT RUNX1. To investigate the leukemogenic effect of mutated RUNX1, H78Q and V91fs-ter94 were transduced into 32D cells or BCR-ABL-harboring murine cells, respectively. Consistent with the myeloblastic features of advanced CML patients with RUNX1 mutations, H78Q and V91fs-ter94 disturbed myeloid differentiation and induced a BC or accelerated phase-like phenotype in mice. These results suggest that RUNX1 abnormalities may promote acute myeloid leukemic transformation in a subset of CML patients.
State Key Laboratory of Medical Genomics, Institute of Health Sciences, Shanghai Institutes for Biological Sciences and Graduate School, Rui Jin Hospital, Shanghai, China.
Li-Juan
LJ
Zhao
Yue-Ying
YY
Wang
Guo
G
Li
Li-Yuan
LY
Ma
Shu-Min
SM
Xiong
Xiang-Qin
XQ
Weng
Wei-Na
WN
Zhang
Bo
B
Wu
Zhu
Z
Chen
Sai-Juan
SJ
Chen
D000293:Adolescent; D000328:Adult; D000818:Animals; D001752:Blast Crisis / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D005260:Female; D006801:Humans; D047468:Immunoprecipitation; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D055815:Young Adult
D050676:Core Binding Factor Alpha 2 Subunit; C493728:RUNX1 protein, human