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Functional features of RUNX1 mutants in acute transformation of chronic myeloid leukemia and their contribution to inducing murine full-blown leukemia.

Authors
  • Zhao, Li-Juan
  • Wang, Yue-Ying
  • Li, Guo
  • Ma, Li-Yuan
  • Xiong, Shu-Min
  • Weng, Xiang-Qin
  • Zhang, Wei-Na
  • Wu, Bo
  • Chen, Zhu
  • Chen, Sai-Juan
Type
Published Article
Journal
Blood
Publisher
American Society of Hematology
Publication Date
Mar 22, 2012
Volume
119
Issue
12
Pages
2873–2882
Identifiers
DOI: 10.1182/blood-2011-08-370981
PMID: 22318203
Source
Medline
License
Unknown

Abstract

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.

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