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

Lucio H Castilla; John H Bushweller

doi:10.1007/978-981-10-3233-2_15

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

Adv Exp Med Biol. 2017:962:229-244. doi: 10.1007/978-981-10-3233-2_15.

Authors

Lucio H Castilla¹, John H Bushweller²

Affiliations

¹ Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, 01605, USA. Lucio.Castilla@umassmed.edu.
² Molecular Physiology and Biophysics, University of Virginia Medical School, Charlottesville, VA, 22908, USA.

PMID: 28299661
DOI: 10.1007/978-981-10-3233-2_15

Abstract

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.

Keywords: AI-10-49; AML; CBF; CBFb-MYH11; CBFbeta-SMMHC; Leukemia; PPI; Protein-protein interaction inhibitor; RUNX1; Targeted therapies; inv(16).

Publication types

Review

MeSH terms

Animals
Core Binding Factor beta Subunit / genetics*
Humans
Leukemia, Myeloid, Acute / genetics*
Leukemia, Myeloid, Acute / pathology*
Myosin Heavy Chains / genetics*
Oncogene Proteins, Fusion / genetics*

Substances

CBFbeta-MYH11 fusion protein
Core Binding Factor beta Subunit
Oncogene Proteins, Fusion
Myosin Heavy Chains