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A cohesive look at leukemogenesis: The cohesin complex and other driving mutations in AML. Neoplasia 2021 Mar;23(3):337-347

Date

02/24/2021

Pubmed ID

33621854

Pubmed Central ID

PMC7905235

DOI

10.1016/j.neo.2021.01.003

Scopus ID

2-s2.0-85101390156   7 Citations

Abstract

Acute myeloid leukemia (AML) affects tens of thousands of patients a year, yet survival rates are as low as 25% in certain populations. This poor survival rate is partially due to the vast genetic diversity of the disease. Rarely do 2 patients with AML have the same mutational profile, which makes the development of targeted therapies particularly challenging. However, a set of recurrent mutations in chromatin modifiers have been identified in many patients, including mutations in the cohesin complex, which have been identified in up to 20% of cases. Interestingly, the canonical function of the cohesin complex in establishing sister chromatid cohesin during mitosis is unlikely to be the affected role in leukemogenesis. Instead, the cohesin complex's role in DNA looping and gene regulation likely facilitates disease. The epigenetic mechanisms by which cohesin complex mutations promote leukemia are not completely elucidated, but alterations of enhancer-promoter interactions and differential histone modifications have been shown to drive oncogenic gene expression changes. Such changes commonly include HoxA upregulation, which may represent a common pathway that could be therapeutically targeted. As cohesin mutations rarely occur alone, examining the impact of common co-occurring mutations, including those in NPM1, the core-binding factor complex, FLT3, and ASXL1, will yield additional insight. While further study of these mutational interactions is required, current research suggests that the use of combinatorial genetics could be the key to uncovering new targets, allowing for the treatment of AML patients based on their individual genetic profiles.

Author List

Heimbruch KE, Meyer AE, Agrawal P, Viny AD, Rao S

Author

Sridhar Rao MD, PhD Associate Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Carrier Proteins
Cell Cycle Proteins
Chromatin
Chromatin Assembly and Disassembly
Chromosomal Proteins, Non-Histone
Disease Susceptibility
Genetic Predisposition to Disease
Humans
Leukemia, Myeloid, Acute
Mutation
Oncogenes
Protein Binding
Protein Multimerization
Structure-Activity Relationship