Dose-dependent role of the cohesin complex in normal and malignant hematopoiesis

Abstract

Viny et al. show that depletion of the cohesin subunit Smc3 affects HSC function through disruption of chromatin structure and that cohesin haploinsufficiency cooperates with Flt3-ITD to induce transformation of stem/progenitor cells and leukemia development.

Cohesin mutations in human cancer

“…The generation of aneuploidy does not appear to be the primary role of cohesin mutations in myeloid malignancies, since many cohesin gene mutations have been identified in euploid samples [55,60,61]. Instead, as described in greater detail below, studies of mouse models have pointed to lineage skewing resulting from aberrant chromatin structure and transcription factor accessibility as a particularly important effect of cohesin mutations in myeloid precursor cells [65,66,67]. …”

“…As described below, two groups have created and studied mice in which individual cohesin genes have been inactivated by either gene targeting or shRNA, and another group has used primarily tissue culture-based approaches [65,66,67]. …”

“…generated SMC3 inducible knockout mice. Induction of knockout in the hematopoietic compartment of adult animals resulted in lethality in 11.5 days [66] with animals exhibiting numerous features that included an absence of myeloid elements in the peripheral blood. Upon heterozygous SMC3 knockout, animals were viable and bone marrow cells demonstrated enhanced self-renewal properties in vitro and in vivo that were especially pronounced when cells were also expressing the FLT3 - ITD mutant (a mutation previously reported to co-occur with cohesin mutations in myeloid malignancies [55].…”

Emerging concepts of epigenetic dysregulation in hematological malignancies

“…Downregulation of cohesin function in mouse or human cells promotes aberrant self-renewal and myeloid skewing of hematopoiesis 25–27 . Given that the most well-established function of the cohesin complex is to regulate the alignment of sister chromatids during mitosis 28 , it was a surprise to find no trace of genomic instability in mouse or human myeloid leukemia.…”

Multiplex CRISPR/Cas9-Based Genome Editing in Human Hematopoietic Stem Cells Models Clonal Hematopoiesis and Myeloid Neoplasia

“…However, there are fundamental differences in tumorigenesis in human versus mouse cells (Rangarajan and Weinberg, 2003), related both to the biology of oncogenes and tumor suppressor genes and to the effects of genetic background and target cells of transformation. The differences between mouse and human cells may be particularly important in the study of somatic mutations in cohesin genes, which regulate long-range DNA looping interactions, due to sequence variation between the species in regulatory elements and chromosome architecture (Mazumdar et al, 2015; Mullenders et al, 2015; Viny et al, 2015). As such, use of genetically engineered mouse models or retroviral transduction of mouse bone marrow cells may not fully capture disease-relevant biology, and these differences suggest the need to develop genetically engineered in vivo models of human myeloid malignancies.…”