Author: Bushweller, John Hackett ; Wolfe, Scot A. ; Belaghzal, Houda ; Muller-Tidow, Carsten ; Illendula, Anuradha ; Ou, Jianhong ; Zhu, Lihua Julie ; Ahmad, Hafiz Mohd ; Hegde, Mahesh ; Dekker, Job ; Castilla, Lucio Hernán ; Pulikkan, John Anto ; O’Hagan, Kelsey ; Yu, Jun

Due to a typesetting error, the version of the article published online omitted the authors′ proof corrections.The article has now been updated online.

01 Jun 2018·CellQ1 · BIOLOGY

CBFβ-SMMHC Inhibition Triggers Apoptosis by Disrupting MYC Chromatin Dynamics in Acute Myeloid Leukemia

Q1 · BIOLOGY

Article

Author: Yu, Jun ; Belaghzal, Houda ; Wolfe, Scot A ; O'Hagan, Kelsey ; Ahmad, Hafiz Mohd ; Dekker, Job ; Castilla, Lucio Hernán ; Illendula, Anuradha ; Hegde, Mahesh ; Muller-Tidow, Carsten ; Bushweller, John Hackett ; Pulikkan, John Anto ; Zhu, Lihua Julie ; Ou, Jianhong

The fusion oncoprotein CBFβ-SMMHC, expressed in leukemia cases with chromosome 16 inversion, drives leukemia development and maintenance by altering the activity of the transcription factor RUNX1. Here, we demonstrate that CBFβ-SMMHC maintains cell viability by neutralizing RUNX1-mediated repression of MYC expression. Upon pharmacologic inhibition of the CBFβ-SMMHC/RUNX1 interaction, RUNX1 shows increased binding at three MYC distal enhancers, where it represses MYC expression by mediating the replacement of the SWI/SNF complex component BRG1 with the polycomb-repressive complex component RING1B, leading to apoptosis. Combining the CBFβ-SMMHC inhibitor with the BET inhibitor JQ1 eliminates inv(16) leukemia in human cells and a mouse model. Enhancer-interaction analysis indicated that the three enhancers are physically connected with the MYC promoter, and genome-editing analysis demonstrated that they are functionally implicated in deregulation of MYC expression. This study reveals a mechanism whereby CBFβ-SMMHC drives leukemia maintenance and suggests that inhibitors targeting chromatin activity may prove effective in inv(16) leukemia therapy.

01 Jan 2017·Advances in Experimental Medicine and BiologyQ4 · MEDICINE

Molecular Basis and Targeted Inhibition of CBFβ-SMMHC Acute Myeloid Leukemia

Q4 · MEDICINE

Review

Author: Castilla, Lucio H ; Bushweller, John H

Acute myeloid leukemia (AML) is characterized by recurrent chromosomal rearrangements that encode for fusion proteins which drive leukemia initiation and maintenance. The inv(16) (p13q22) rearrangement is a founding mutation and the associated CBFβ-SMMHC fusion protein is essential for the survival of inv(16) AML cells. This Chapter will discuss our understanding of the function of this fusion protein in disrupting hematopoietic homeostasis and creating pre-leukemic blasts, in its cooperation with other co-occurring mutations during leukemia initiation, and in leukemia maintenance. In addition, this chapter will discuss the current approaches used for the treatment of inv(16) AML and the recent development of AI-10-49, a selective targeted inhibitor of CBFβ-SMMHC/RUNX1 binding, the first candidate targeted therapy for inv(16) AML.

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Indication	Highest Phase	Country/Location	Organization	Date
Acute Myeloid Leukemia	Preclinical	United States	University of Virginia	13 Feb 2015

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