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DOT1L inhibitors block abnormal self-renewal induced by cohesin loss. Sci Rep 2021 Mar 31;11(1):7288

Date

04/02/2021

Pubmed ID

33790356

Pubmed Central ID

PMC8012605

DOI

10.1038/s41598-021-86646-9

Scopus ID

2-s2.0-85103745135   4 Citations

Abstract

Acute myeloid leukemia (AML) is a high-risk malignancy characterized by a diverse spectrum of somatic genetic alterations. The mechanisms by which these mutations contribute to leukemia development and how this informs the use of targeted therapies is critical to improving outcomes for patients. Importantly, how to target loss-of-function mutations has been a critical challenge in precision medicine. Heterozygous inactivating mutations in cohesin complex genes contribute to AML in adults by increasing the self-renewal capacity of hematopoietic stem and progenitor cells (HSPCs) by altering PRC2 targeting to induce HOXA9 expression, a key self-renewal transcription factor. Here we sought to delineate the epigenetic mechanism underpinning the enhanced self-renewal conferred by cohesin-haploinsufficiency. First, given the substantial difference in the mutational spectrum between pediatric and adult AML patients, we first sought to identify if HOXA9 was also elevated in children. Next, using primary HSPCs as a model we demonstrate that abnormal self-renewal due to cohesin loss is blocked by DOT1L inhibition. In cohesin-depleted cells, DOT1L inhibition is associated with H3K79me2 depletion and a concomitant increase in H3K27me3. Importantly, we find that there are cohesin-dependent gene expression changes that promote a leukemic profile, including HoxA overexpression, that are preferentially reversed by DOT1L inhibition. Our data further characterize how cohesin mutations contribute to AML development, identifying DOT1L as a potential therapeutic target for adult and pediatric AML patients harboring cohesin mutations.

Author List

Heimbruch KE, Fisher JB, Stelloh CT, Phillips E, Reimer MH Jr, Wargolet AJ, Meyer AE, Pulakanti K, Viny AD, Loppnow JJ, Levine RL, Pulikkan JA, Zhu N, Rao S

Authors

John A. Pulikkan PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
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
Benzimidazoles
Cell Cycle Proteins
Cell Self Renewal
Cells, Cultured
Chromosomal Proteins, Non-Histone
Enzyme Inhibitors
Epigenesis, Genetic
Hematopoietic Stem Cells
Histone-Lysine N-Methyltransferase
Histones
Homeodomain Proteins
Humans
Leukemia, Myeloid, Acute
Mice