Transcriptional regulators, including the cohesin complex member STAG2, are recurrently mutated in cancer. The role of STAG2 in gene regulation, hematopoiesis, and tumor suppression remains unresolved. We show that Stag2 deletion in hematopoietic stem and progenitor cells (HSPCs) results in altered hematopoietic function, increased selfrenewal, and impaired differentiation. Chromatin immunoprecipitation (ChIP) sequencing revealed that, although Stag2 and Stag1 bind a shared set of genomic loci, a component of Stag2 binding sites is unoccupied by Stag1, even in Stag2-deficient HSPCs. Although concurrent loss of Stag2 and Stag1 abrogated hematopoiesis, Stag2 loss alone decreased chromatin accessibility and transcription of lineage-specification genes, including Ebf1 and Pax5, leading to increased self-renewal and reduced HSPC commitment to the B cell lineage. Our data illustrate a role for Stag2 in transformation and transcriptional dysregulation distinct from its shared role with Stag1 in chromosomal segregation.

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Transcriptional regulators, including the cohesin complex member STAG2, are recurrently mutated in cancer. The role of STAG2 in gene regulation, hematopoiesis, and tumor suppression remains unresolved. We show Stag2 deletion in hematopoietic stem/progenitor cells (HSPC) results in altered hematopoietic function, increased selfrenewal, and impaired differentiation. ChIP-sequencing revealed that while Stag2 and Stag1 can bind the same loci, a component of Stag2 binding sites are unoccupied by Stag1 even in Stag2-deficient HSPCs. While concurrent loss of Stag2 and Stag1 abrogated hematopoiesis, Stag2 loss alone decreased chromatin accessibility and transcription of lineage-specification genes, including Ebf1 and Pax5, leading to blunted HSPC commitment to the B-cell lineage. Our data illustrate a role for Stag2 in transformation and transcriptional dysregulation distinct from its shared role with Stag1 in chromosomal segregation.One Sentence Summary: Stag1 rescues topologically associated domains in the absence of Stag2, but cannot restore chromatin architecture required for hematopoietic lineage commitment 3 Main textCell-type specific transcriptional programs are regulated in part by the activity of tissue-specific transcription factors and enhancer elements within structurally defined topologically associating domains (TADs) (1-3). The genes which contribute to transcriptional regulation, including members of the cohesin complex, are frequently mutated in human cancers, including 5 leukemias(4-9). Cohesin is a tripartite ring comprised of three structural proteins SMC1A, SMC3, and RAD21; this core complex binds to either STAG1 or STAG2. STAG2, which is an X-linked gene, is the most commonly mutated cohesin complex member in human cancer, with recurrent nonsense, frameshift, and missense mutations in Ewing's Sarcoma (40-60%)(9), bladder cancer (20-35%)(7, 8), glioblastoma (4-5%)(7), myelodysplastic syndrome (MDS)(5-20%)(5, 6), and 10 acute myeloid leukemia (AML)(2-12%)(5). This is in contrast to SMC1A, SMC3, and RAD21, which are more commonly mutated in myeloid malignancies than in a broad spectrum of human cancers. The cohesin complex is essential in pleiotropic cellular and gene regulatory functions, including chromosome segregation(10, 11) and in the formation of DNA loops (3,(12)(13)(14) which regulate gene expression (13,15, 16). However, the high mutational frequency and unique 15 mutational spectrum of STAG2 in human cancers(5-7) suggests a distinct role in homeostasis and tumor suppression(17, 18) which has not been delineated.

Highlights PARP inhibitors (PARPi) reduce the risk of ovarian cancer progression and recurrence after response to platinum chemotherapy. Rarely, PARPi are associated with increased risk of hematologic malignancies (MDS/AML) in some patients with ovarian cancer. The causal relationship between PARPi and leukemogenesis is unclear but may be associated with cumulative chemotherapy. We present 3 patients with germline BRCA -associated ovarian cancer and mutations potentially associated with risk of MDS/AML. The clinical benefit of PARPi should be viewed with caution in patients with elevated baseline risk of developing MDS/AML.

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