Highlights from

ASH 2019

61st Annual Meeting & Exposition of the American Society of Hematology

Orlando, Florida (USA) 7 - 10 December 2019

Experimental model for limitations of haematopoietic stem cells propagation

Dr Jennifer Myers SanMiguel (The Jackson Laboratory, USA) presented a novel mechanism of cell-extrinsic stressors emerging from the ageing bone marrow microenvironment in promoting Dnmt3a-mutant clonal haematopoiesis [1].

The knowledge gap that Dr SanMiguel and colleagues attempted to address was how self-renewal of somatic stem cells such as haematopoietic stem cells (HSCs) are limited in their repopulation ability. A molecular clue from several studies point to DNA methylase DNA (cytosine-5)-methyltransferase 3A (Dnmt3a). Loss of the Dnmt3a gene removes self-renewal limits allowing indefinite HSC propagation in vivo.

Dr SanMiguel and colleagues examined the role of HSC-extrinsic stressors in overcoming the impaired differentiation of Dnmt3a-mutant HSCs. Using bone marrow from young Dnmt3aR878H/+ mice into young and old congenic recipient mice, she noted an accelerated expansion of phenotypically defined Dnmt3aR878H/+ short-term HSCs and their progeny. The researchers then re-isolated the Dnmt3aR878H/+ long-term HSCs from both young and aged mice and found upregulated gene signatures associated with pro-myeloid differentiation on global transcriptome analysis from the aged bone marrow microenvironment.

RNA sequencing identified elevated levels of tumour necrosis factor-α and macrophage colony-stimulating factor in the aged bone marrow microenvironment. Using an ex vivo culture system, extrinsic application of these 2 cytokines overcame the differentiation block in Dnmt3aR878H/+ long-term HSCs and favoured the expansion toward the pro-myeloid phenotype. Blocking these cytokines using an agent like the anti-tumour necrosis factor agent etanercept reversed the clonal haematopoiesis expansion in these preclinical models. Furthermore, NPM1 mutation drives evolution of Dnmt3a-mutant clonal haematopoiesis to acute myeloid leukaemia, and the rate of disease progression is accelerated with longer latency of clonal haematopoiesis.

Dr SanMiguel concluded that understanding the ageing-associated stressors in the bone marrow microenvironment to propagate the clonal haematopoiesis could translate to human disease by offering novel molecular targets to prevent clonal haematopoiesis expansion.

Keywords: Haematopoietic Stem Cells; Dnmt3a; Tumour Necrosis Factor-alpha; Macrophage Colony-Stimulating Factor; Ageing; Bone Marrow; Haematopoiesis

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