Cohesin mutations alter DNA damage repair and chromatin structure and create therapeutic vulnerabilities in MDS/AML
Zuzana Tothova, … , Job Dekker, Benjamin L. Ebert
Zuzana Tothova, … , Job Dekker, Benjamin L. Ebert
Published December 22, 2020
Citation Information: JCI Insight. 2021;6(3):e142149. https://doi.org/10.1172/jci.insight.142149.
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Research Article Hematology Oncology

Cohesin mutations alter DNA damage repair and chromatin structure and create therapeutic vulnerabilities in MDS/AML

Abstract

The cohesin complex plays an essential role in chromosome maintenance and transcriptional regulation. Recurrent somatic mutations in the cohesin complex are frequent genetic drivers in cancer, including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Here, using genetic dependency screens of stromal antigen 2–mutant (STAG2-mutant) AML, we identified DNA damage repair and replication as genetic dependencies in cohesin-mutant cells. We demonstrated increased levels of DNA damage and sensitivity of cohesin-mutant cells to poly(ADP-ribose) polymerase (PARP) inhibition. We developed a mouse model of MDS in which Stag2 mutations arose as clonal secondary lesions in the background of clonal hematopoiesis driven by tet methylcytosine dioxygenase 2 (Tet2) mutations and demonstrated selective depletion of cohesin-mutant cells with PARP inhibition in vivo. Finally, we demonstrated a shift from STAG2- to STAG1-containing cohesin complexes in cohesin-mutant cells, which was associated with longer DNA loop extrusion, more intermixing of chromatin compartments, and increased interaction with PARP and replication protein A complex. Our findings inform the biology and therapeutic opportunities for cohesin-mutant malignancies.

Authors

Zuzana Tothova, Anne-Laure Valton, Rebecca A. Gorelov, Mounica Vallurupalli, John M. Krill-Burger, Amie Holmes, Catherine C. Landers, J. Erika Haydu, Edyta Malolepsza, Christina Hartigan, Melanie Donahue, Katerina D. Popova, Sebastian Koochaki, Sergey V. Venev, Jeanne Rivera, Edwin Chen, Kasper Lage, Monica Schenone, Alan D. D’Andrea, Steven A. Carr, Elizabeth A. Morgan, Job Dekker, Benjamin L. Ebert

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Figure 4

Talazoparib treatment preferentially depletes cohesin-mutant clones in primary mouse and human cell in vivo models of cohesin-mutant myeloid diseases.

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Talazoparib treatment preferentially depletes cohesin-mutant clones in p...
(A) Schematic of the in vivo drug treatment of Tet2/NTG and Tet2/Stag2-mutant mice with talazoparib. (B) Bone marrow analysis of Stag2 and Tet2 indel fraction by NGS demonstrates a genotype-specific response to talazoparib treatment in Tet2/Stag2 but not Tet2/NTG-mutant clones. Mean ± SD is shown. P values were determined using Student’s t test. n = 10 mice/group. (C) Complete blood count analysis shows normalization of the WBC, monocyte, and platelet counts in talazoparib-treated Tet2/Stag2 animals. Mean ± SD is shown. P values were determined using Student’s t test. n = 10 mice/group. (D) Morphologic evaluation of bone marrow of representative Tet2/Stag2-mutant mice treated with talazoparib or DMSO shows an increased megakaryocyte number and persistent erythrophagocytosis in Tet2/Stag2-mutant mice treated with talazoparib. Images were stained using H&E and imaged at 10× (scale bar: 0.5 mm) and 40× (scale bar: 0.125 mm) original magnification. (E) Generation of a STAG2-mutant AML PDX model in NSGS mice. Staining with H&E, modified Giemsa May-Grünwald (MGG), and immunohistochemistry shows expansion of immature CD45+CD34+CD33+ myeloid blasts in the bone marrow. Images were taken using 10× (scale bar: 0.5 mm) and 100× original magnification (scale bar: 0.05 mm). (F) Schematic of the in vivo drug treatment of STAG2-mutant AML PDX model. Mice howed a decrease in spleen size and human CD45+ bone marrow disease burden in the talazoparib-treated arm. Mean ± SD is shown. P values were determined using Student’s t test. n = 9–10 mice/group. (G) Schematic of the in vivo drug treatment of RAD21-mutant AML PDX model. Treatment with talazoparib led to a decrease in spleen size and improved overall survival. Mean ± SD is shown. P values were determined using Student’s t test and Kaplan-Meier survival analysis. n = 4 mice/group.