[PDF][PDF] Accelerated leukemogenesis by truncated CBFβ-SMMHC defective in high-affinity binding with RUNX1

Y Kamikubo, L Zhao, M Wunderlich, T Corpora… - Cancer cell, 2010 - cell.com
Y Kamikubo, L Zhao, M Wunderlich, T Corpora, RK Hyde, TA Paul, M Kundu, L Garrett…
Cancer cell, 2010cell.com
Dominant RUNX1 inhibition has been proposed as a common pathway for CBF leukemia.
CBFβ-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 CBFβ-SMMHC fusion in AML patients lacks HABD. Here, we report that the type I
CBFβ-SMMHC protein binds RUNX1 inefficiently. Knockin mice expressing CBFβ-SMMHC
with a HABD deletion developed leukemia quickly, even though hematopoietic defects …
Summary
Dominant RUNX1 inhibition has been proposed as a common pathway for CBF leukemia. CBFβ-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 CBFβ-SMMHC fusion in AML patients lacks HABD. Here, we report that the type I CBFβ-SMMHC protein binds RUNX1 inefficiently. Knockin mice expressing CBFβ-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 CBFβ-SMMHC.
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