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 Dnmt3a^R878H/+ mice into young and old congenic recipient mice, she noted an accelerated expansion of phenotypically defined Dnmt3a^R878H/+ short-term HSCs and their progeny. The researchers then re-isolated the Dnmt3a^R878H/+ 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 Dnmt3a^R878H/+ 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.

1. SanMiguel J, et al. Abstract 5, ASH 2019, 7-10 December, Orlando, USA.

Posted on 5 March 202016 February 2024