Accelerated Leukemogenesis by Truncated CBF Beta-SMMHC Defective in High-affinity Binding with RUNX1

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2010 May 19

PMID 20478528

Citations 29

Authors

Yasuhiko Kamikubo

Ling Zhao

Mark Wunderlich

Takeshi Corpora

R Katherine Hyde

Thomas A Paul

Mondira Kundu

Lisa Garrett

Sheila Compton

Gang Huang

Linda Wolff

Yoshiaki Ito

John Bushweller

James C Mulloy

P Paul Liu

Affiliations

Soon will be listed here.

Abstract

Dominant RUNX1 inhibition has been proposed as a common pathway for CBF leukemia. CBF beta-SMMHC, a fusion protein in human acute myeloid leukemia (AML), dominantly inhibits RUNX1 largely through its RUNX1 high-affinity binding domain (HABD). However, the type I CBF beta-SMMHC fusion in AML patients lacks HABD. Here, we report that the type I CBF beta-SMMHC protein binds RUNX1 inefficiently. Knockin mice expressing CBF beta-SMMHC with a HABD deletion developed leukemia quickly, even though hematopoietic defects associated with Runx1-inhibition were partially rescued. A larger pool of leukemia-initiating cells, increased MN1 expression, and retention of RUNX1 phosphorylation are potential mechanisms for accelerated leukemia development in these mice. Our data suggest that RUNX1 dominant inhibition may not be a critical step for leukemogenesis by CBF beta-SMMHC.

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