Identifying synthetic lethal drugs for cohesin mutant AML — ASN Events

Identifying synthetic lethal drugs for cohesin mutant AML (#174)

Alice Chin 1 , Jisha Antony 1 , Julia Horsfield 1
  1. Department of Pathology, University of Otago, Dunedin, New Zealand

Acute myeloid leukaemia (AML) is an aggressive blood cancer, characterized by the accumulation of abnormal myeloid progenitor cells in the bone marrow and blood. Recent studies of mutational landscape of AML patients using whole-exome sequencing identified cohesin complex genes as frequently mutated AML genes [1, 2]. Cohesin mutations are also often found in other myeloid leukaemias such as Down Syndrome related-acute megakaryocytic leukaemia [3], and in other cancer types such as glioblastoma [4], Ewing’s sarcoma [5] and melanoma [6]. This highlights the important role of cohesin mutations in leukemogenesis and cancer. However, the precise details of how cohesin mutations contribute to leukemogenesis remains to be defined.

The cohesin complex is best known for its role in sister chromatid cohesion during mitosis, and comprises of four essential subunits, RAD21, STAG2, SMC3 and SMC1A. Despite its cell division function, cohesin mutation in cancer are not usually associated with chromosomal instability or complex cytogenetics [7], but rather, with altered gene expression and cell differentiation blockade. In zebrafish, heterozygous loss of cohesin subunits, RAD21or SMC3 alters expression of runx1 [8], a gene crucial for haematopoiesis. Heterozygous cohesin mutations also alter hematopoietic stem cells (HSCs) differentiation [9-11]  and promote a stem-cell-like gene expression signature [12]. Cohesin mutations also occur early in the development of AML [7], making it an ideal target for drug development.

We aim to use synthetic lethal approach to antagonise the survival of cohesin-deficient cells. We hypothesize that cohesin mutations alone does not lead to cell death in cancer cells, but will render cells vulnerable to inhibition of biological pathways that depend on cohesin. By using synthetic lethal targeting, selective killing of cohesin-mutant cancer cells can be achieved while sparing the normal cells. To model heterozygous loss of cohesin as seen in AML, we are using MCF10A cells with cohesin gene mutations (RAD21 and SMC3) as a platform for high throughput drug screening. Our results show that heterozygous Smc3 mutations confer proliferative advantage in MCF10A cells. Preliminary evidence suggests that cohesin mutations sensitise MCF10A cells to drugs targeting mTOR and the DNA damage repair pathway. In summary, synthetic lethal screening provides an effective approach in identifying drugs for cancer cells harbouring cohesin mutations.

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