Inflammatory signals from fatty bone marrow supports the early stages of DNMT3a driven clonal hematopoiesis

Abstract

Age related cancer is not only due to the random accumulation of mutations, but also how phenotypes are selected by the aging environment. While fatty bone marrow (FBM), is one of the hallmarks of bone marrow ageing, it is unknown whether FBM can modify the evolution of the early stages of leukemia and clonal hematopoiesis (CH). To address this question, we established FBM mice models and transplanted both human and mice preleukemic hematopoietic stem cells (PreL-HSCs) carrying DNMT3A mutations. We demonstrate that castration which models age related andropenia result in FBM. A significant increase in self-renewal was found when DNMT3AMut-preL-HSPCs were exposed to FBM. To better understand the mechanisms of the FBM-preL-HSPCs interaction, we performed single cell RNA-sequencing on HSPCs three days after FBM exposure. A 20-50 fold increase in DNMT3AMut-preL-HSCs was observed under FBM conditions in comparison to other conditions. PreL-HSPCs exposed to FBM exhibited an activated inflammatory signaling (IL-6 and INFγ). Cytokine analysis of BM fluid demonstrated increased IL-6 levels under FBM conditions. Anti-IL-6 neutralizing antibodies significantly reduced the selective advantage of DNMT3AMut-preL-HSPCs exposed to FBM. Overall, age related paracrine FBM inflammatory signals promote DNMT3A-driven clonal hematopoiesis, which can be inhibited by blocking the IL-6 receptor.

Age-related micro-environmental changes as drivers of clonal hematopoiesis

“…This effect was mediated by the secretion of IL-6 from the FBM microenvironment. Co-culturing of DNM3A mutated preL-HSPCs with IL-6 increased their ability to generate CFU colonies, and anti-IL-6 neutralizing antibodies significantly reduced the selective advantage of DNMT3A mutated-HSCs exposed to FBM [35 ▪▪ ]. This suggests that the FBM plays a role in shaping the clonal expansion of preleukemic DNMT3A mutated clones.…”

“…In addition to the interactions between FBM and leukemia, novel insights have recently been gained regarding the effects of FBM on preleukemic evolution. We provide evidence that FBM interacts with human preleukemic HSPCs (preL-HSPCs) carrying DNMT3A mutations, giving them a selective advantage and potentially enhancing the ability of mice preL-HSPCs carrying DNMT3A mutations to self-renew [35 ▪▪ ]. This effect was mediated by the secretion of IL-6 from the FBM microenvironment.…”

“…Ovariectomy (OVX) in mice leads to increased FBM, which can be reversed by estrogen supplement [39]. In a similar way, castration in mice leads to FBM [35 ▪▪ ]. In human, estrogen treatment in postmenopausal women reduces FBM [40], whereas studies on testosterone treatment are still lacking.…”

Monocyte-derived microglia withDnmt3amutation cause motor pathology in aging mice

“…To probe for the impact of a CH-associated somatic mutation on MoMg functions in the CNS and potential consequences on brain physiology, we took advantage of a mouse model that harbors a replacement of the murine Dnmt3a gene with a cDNA encoding the human DNMT3A R882H variant 49,50 . Upon introduction of a Vav Cre allele, HSC of these animals express hDNMT3A R882H which alters, as reported for human cells 51,52 with time the HSPC methylome 49 .…”

Obesity, bone marrow adiposity, and leukemia: Time to act

“…This alteration in the BM structure, function, and cellular architecture may lead to leukemia. For example, fatty BM (FBM) as observed in people with obesity have increased IL‐6 in their BM fluid and BM adipocytes (BM‐As), which by paracrine signals promotes DNA (cytosine‐5)‐methyltransferase 3A (DNMT3A, responsible for de novo DNA methylation) upregulation and clonal hematopoiesis (CH) 21 . DNMT3A plays a critical role in hematopoietic stem cell (HPSC) differentiation, hematological malignancies, and leukemia, including acute myeloid leukemia (AML) 22–25 .…”