Accelerated Leukemogenesis by Truncated CBFβ-SMMHC Defective in High-Affinity Binding with RUNX1

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

doi:10.1016/j.ccr.2010.03.022

Accelerated Leukemogenesis by Truncated CBFβ-SMMHC Defective in High-Affinity Binding with RUNX1

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

Research output: Contribution to journal › Article › peer-review

40 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	455-468
Number of pages	14
Journal	Cancer Cell
Volume	17
Issue number	5
DOIs	https://doi.org/10.1016/j.ccr.2010.03.022
State	Published - May 18 2010
Externally published	Yes

Keywords

CELLCYCLE

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

Access to Document

10.1016/j.ccr.2010.03.022

Cite this

@article{99f1c73b719344649e9f9271d3c03ca0,

title = "Accelerated Leukemogenesis by Truncated CBFβ-SMMHC Defective in High-Affinity Binding with RUNX1",

abstract = "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.",

keywords = "CELLCYCLE",

author = "Yasuhiko Kamikubo and Ling Zhao and Mark Wunderlich and Takeshi Corpora and Hyde, {R. Katherine} and Paul, {Thomas A.} and Mondira Kundu and Lisa Garrett and Sheila Compton and Gang Huang and Linda Wolff and Yoshiaki Ito and John Bushweller and Mulloy, {James C.} and Liu, {P. Paul}",

note = "Funding Information: We thank M. Kirby and S. Anderson for FACS analysis, B.A. van der Reijden for the human leukemia sample, C. Wang for statistical analysis of microarray data, A. Elkahloun for microarray hybridization, K. Brewery for the cytokine TPO, and Amgen for FLT3L, SCF, and IL-6. This work was supported by the Intramural Research Programs of National Human Genome Research Institute, NIH, NIH grant CA118319, U.S.P.H.S. Grant Number MO1 RR 08084, and General Clinical Research Centers Program, National Center for Research Resources, NIH. ",

year = "2010",

month = may,

day = "18",

doi = "10.1016/j.ccr.2010.03.022",

language = "English (US)",

volume = "17",

pages = "455--468",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "5",

}

TY - JOUR

T1 - Accelerated Leukemogenesis by Truncated CBFβ-SMMHC Defective in High-Affinity Binding with RUNX1

AU - Kamikubo, Yasuhiko

AU - Zhao, Ling

AU - Wunderlich, Mark

AU - Corpora, Takeshi

AU - Hyde, R. Katherine

AU - Paul, Thomas A.

AU - Kundu, Mondira

AU - Garrett, Lisa

AU - Compton, Sheila

AU - Huang, Gang

AU - Wolff, Linda

AU - Ito, Yoshiaki

AU - Bushweller, John

AU - Mulloy, James C.

AU - Liu, P. Paul

N1 - Funding Information: We thank M. Kirby and S. Anderson for FACS analysis, B.A. van der Reijden for the human leukemia sample, C. Wang for statistical analysis of microarray data, A. Elkahloun for microarray hybridization, K. Brewery for the cytokine TPO, and Amgen for FLT3L, SCF, and IL-6. This work was supported by the Intramural Research Programs of National Human Genome Research Institute, NIH, NIH grant CA118319, U.S.P.H.S. Grant Number MO1 RR 08084, and General Clinical Research Centers Program, National Center for Research Resources, NIH.

PY - 2010/5/18

Y1 - 2010/5/18

N2 - 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.

AB - 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.

KW - CELLCYCLE

UR - http://www.scopus.com/inward/record.url?scp=77952109450&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77952109450&partnerID=8YFLogxK

U2 - 10.1016/j.ccr.2010.03.022

DO - 10.1016/j.ccr.2010.03.022

M3 - Article

C2 - 20478528

AN - SCOPUS:77952109450

SN - 1535-6108

VL - 17

SP - 455

EP - 468

JO - Cancer Cell

JF - Cancer Cell

IS - 5

ER -

Accelerated Leukemogenesis by Truncated CBFβ-SMMHC Defective in High-Affinity Binding with RUNX1

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this