Cohesin mutations in myeloid malignancies: underlying mechanisms

Abstract

Recently, whole genome sequencing approaches have pinpointed mutations in genes that were previously not associated with cancer. For Acute Myeloid Leukaemia (AML), and other myeloid disorders, these approaches revealed a high prevalence of mutations in genes encoding the chromosome cohesion complex, cohesin. Cohesin mutations represent a novel genetic pathway for AML, but how AML arises from these mutations is unknown. This review will explore the potential mechanisms by which cohesin mutations contribute to AML and other myeloid malignancies.

Cohesin modulates transcription of estrogen-responsive genes

“…In human syndromes resulting from cohesin mutations, small changes in the amount of functional cohesin can lead to developmental pathology [11], and in cancers, heterozygous mutations in cohesin genes appear to contribute to disease progression [30,33]. Furthermore, cohesin exerts biphasic effects on gene transcription in Drosophila [81] thus; the same gene can increase or decrease its transcriptional response according to cohesin dose.…”

Epigenetic alterations in acute myeloid leukemias

“…On the basis of the report from the genome atlas research network,~13% of AML cases have mutations in cohesin complex components, and these mutations have been mainly found in patients with M1 and M2 FAB subtypes [95]. There is some evidence that alterations of the cohesin complex are initiating events in leukemogenesis [96]. Mutations of cohesin co-occur with NPM1, TET2, DNMT3A and RUNX1 mutations.…”

“…Therefore, it might be that loss-of-function mutations in cohesin lead to transcriptional alteration of genes that have important roles in differentiation and proliferation, eventually leading to clonal evolution and tumorigenesis [98]. In the case of AML, cohesin mutations lead to loss of chromosome interactions between conserved regulatory elements and promoters at specific hematopoietic genes, such as RUNX1: the deregulation of hematopoietic transcription programs could facilitate the development of AML [96].…”

Conditional mutation of Smc5 in mouse embryonic stem cells perturbs condensin localization and mitotic progression

“…Furthermore, SMC mutations are associated with cancer (Leiserson et al, 2015;Jacome et al, 2015). Cohesin mutations have been identified in myeloid leukemias (Leeke et al, 2014). The condensin component Smc2 and the Smc5/6 complex component Smc6 are overexpressed in cancers, such as colorectal, neuroblastoma and breast cancer (Davalos et al, 2012;Murakami-Tonami et al, 2014;Stevens et al, 2011).…”