Cohesin loss and MLL-AF9 are not synthetic lethal in murine hematopoietic stem and progenitor cells

TL;DR

The study found that cohesin loss and MLL-AF9 mutations do not work together to kill hematopoietic cells, suggesting they share a common mechanism.

Contribution

The paper challenges the assumption of synthetic lethality between cohesin mutations and MLL-AF9 in leukemia cells.

Findings

Cohesin subunit loss had minimal impact on MLL-AF9-expressing cells' self-renewal.

Cohesin and MLL fusion mutations may share a mechanism through HOXA gene upregulation.

Lack of cohesin mutations in MLL-rearranged leukemias may reflect shared mechanisms, not synthetic lethality.

Abstract

Objective
As cohesin mutations are rarely found in MLL-rearranged acute myeloid leukemias, we investigated the potential synthetic lethality between cohesin mutations and MLL-AF9 using murine hematopoietic stem and progenitor cells.
Results
Contrary to our hypothesis, a complete loss of
Stag2
or haploinsufficiency of
Smc3
were well tolerated in MLL-AF9-expressing hematopoietic stem and progenitor cells. Minimal effect of cohesin subunit loss on the
in vitro
self-renewal of MLL-AF9-expressing cells was observed. Despite the differing mutational landscapes of cohesin-mutated and MLL fusion AMLs, previous studies showed that cohesin and MLL fusion mutations similarly drive abnormal self-renewal through
HOXA
gene upregulation. The utilization of a similar mechanism suggests that little selective pressure exists for the acquisition of cohesin mutations in AMLs expressing MLL fusions, explaining their lack of co-occurrence. Our results emphasize the importance of using genetic models to test suspected synthetic lethality and suggest that a lack of co-occurrence may instead point to a common mechanism of action between two mutations.