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932 Relocalization of PU.1 Underlies the On- and Off-Tumor Effects of SWI/SNF Blockade in AML

Program: Oral and Poster Abstracts
Type: Oral
Session: 604. Molecular Pharmacology and Drug Resistance: Myeloid Neoplasms: Immune Signaling and Antibody-therapeutic Targeting in Myeloid Neoplasms
Hematology Disease Topics & Pathways:
Research, Acute Myeloid Malignancies, AML, Translational Research, Non-Biological therapies, hematopoiesis, Diseases, Therapies, Myeloid Malignancies, Pharmacology, Biological Processes
Monday, December 12, 2022: 4:45 PM

Courtney Chambers1*, Kristen Kurtz, MD2,3*, Andrew Henry Lewis, PhD4, Katharina Wohlan, PhD5, Yuen San Chan, PhD1*, Katerina Cermakova, PhD1*, Milan Dejmek, PhD6*, Michal Sala, PhD6*, Rogelio Aguilar7*, Mario Loeza Cabrera1*, Radim Nencka, PhD6*, H. Daniel Lacorazza, PhD8, Rachel E. Rau, MD9,10 and H. Courtney Hodges, PhD1,11,12*

1Department of Molecular and Cellular Biology, Center for Precision Environmental Health, and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX
2Texas Children's Hospital, Houston, TX
3Department of Pediatrics, Baylor College of Medicine, Houston, TX
4Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX
5Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston
6Institute of Organic Chemistry and Biochemistry, Prague, CZE
7Baylor College of Medicine, Houston, TX
8Texas Children’s Hospital, Department of Pathology & Immunology, Baylor College of Medicine Texas Children's Hospital, Houston, TX
9Texas Children’s Cancer and Hematology Centers, Department of Pediatrics, Texas Childrens Hospital, Houston, TX
10Department of Pediatrics, Baylor College of Medicine, Houston
11Department of Bioengineering, Rice University, Houston, TX
12Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, TX

SWI/SNF ATP-dependent chromatin remodeling activity has been identified as a strong dependency of acute myeloid leukemia (AML). In AML cell lines, genetic knockdown or chemical inhibition of the SWI/SNF ATPases SMARCA4 (BRG1) or SMARCA2 (BRM) by the selective small-molecule inhibitor BRM014 reduces proliferation and induces leukemic differentiation. These effects arise because SWI/SNF inhibition reduces DNA accessibility at binding sites of PU.1, a factor essential for driving high levels of MYC in leukemic cells.

However, given that both SWI/SNF and PU.1 are essential in hematopoietic development, important questions regarding the use of SWI/SNF inhibitors against AML remain. First, the chromatin features that influence SWI/SNF-dependent PU.1 regulation within healthy hematologic and leukemic cells have not been established. Furthermore, the ability of SWI/SNF inhibitors to target leukemic cells within the bone marrow has remained uncertain, and the effects of these drugs in an immunocompetent setting have not been reported, despite the essential functions of SWI/SNF and PU.1 in normal hematopoiesis. Finally, the sensitivity of primary human AML samples and normal hematopoietic cells has also not been established. As a result, many questions regarding the nature of the therapeutic window for SWI/SNF inhibition against AML have remained unresolved.

Here we evaluate SWI/SNF inhibition using BRM014 in clinically relevant models and examine the consequences of the deregulation of SWI/SNF-dependent PU.1 sites. We demonstrate that inhibition of SWI/SNF shifts PU.1 occupancy from enhancers to promoters in both leukemic and healthy hematopoietic cells. In AML, the shift of PU.1 away from enhancers to the promoters of differentiation-related genes results in loss of MYC expression and differentiation of leukemic cells. In non-leukemic mice, SWI/SNF inhibition suppresses PU.1-dependent B cell development and bone marrow-derived monocyte populations, reflecting off-tumor effects caused by SWI/SNF-dependent PU.1 relocalization. These effects influence peripheral immune cells, as well lineage-committed hematopoietic progenitors within the bone marrow. Moreover, we observe profound therapeutic response to SWI/SNF inhibition in an immunocompetent AML mouse model (Figure 1). In vivo, BRM014 induces differentiation of peripheral leukemic blasts and reduces the leukemic stem cell burden in bone marrow but also induces lymphocytopenia due to its off-tumor effects on PU.1. Nevertheless, the robust regression of leukemic burden seen in vivo over a short two-week treatment period provides a compelling justification for continued study of SWI/SNF inhibitors in the treatment of AML.

Further, response of primary human CD34+ hematopoietic stem and progenitor cells (HSPCs) and AML specimens highlight that normal hematopoiesis is affected at concentrations similar to those needed for therapeutic response in AML (Figure 2). Hence, hematopoietic and immune-related side effects, particularly at higher doses and over the duration of treatment, will be important considerations for clinical use of SWI/SNF inhibitors against AML and other tumors. Overall, our results reveal a variable therapeutic window for SWI/SNF blockade in AML and highlight important off-tumor effects of such therapies in immunocompetent settings.

Disclosures: Lewis: Marker Therapeutics, Inc.: Current Employment. Rau: Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie Pharmaceuticals: Other: Spouse is employee and stock holder.

*signifies non-member of ASH