Classical driver mutations in acute myeloid leukemia (AML) typically affect regulators
of cell proliferation, differentiation, and survival. The selective advantage of increased
proliferation, improved survival, and reduced differentiation on leukemia progression is
immediately obvious. Recent large-scale sequencing efforts have uncovered numerous
novel AML-associated mutations. Interestingly, a substantial fraction of the most
frequently mutated genes encode general regulators of transcription and chromatin
state. Understanding the selective advantage conferred by these mutations remains a
major challenge. A striking example are mutations in genes of the cohesin complex,
a major regulator of three-dimensional genome organization. Several landmark studies
have shown that cohesin mutations perturb the balance between self-renewal and
differentiation of hematopoietic stem and progenitor cells (HSPC). Emerging data now
begin to uncover the molecular mechanisms that underpin this phenotype. Among
these mechanisms is a role for cohesin in the control of inflammatory responses in
HSPCs and myeloid cells. Inflammatory signals limit HSPC self-renewal and drive
HSPC differentiation. Consistent with this, cohesin mutations promote resistance to
inflammatory signals, and may provide a selective advantage for AML progression.
In this review, we discuss recent progress in understanding cohesin mutations in
AML, and speculate whether vulnerabilities associated with these mutations could be
exploited therapeutically