Acute myeloid leukaemia disrupts endogenous myelo-erythropoiesis by compromising the adipocyte bone marrow niche

Abstract

Acute myeloid leukaemia (AML) is distinguished by the generation of dysfunctional leukaemic blasts, and patients characteristically suffer from fatal infections and anaemia due to insufficient normal myelo-erythropoiesis. Direct physical crowding of bone marrow (BM) by accumulating leukaemic cells does not fully account for this haematopoietic failure. Here, analyses from AML patients were applied to both in vitro co-culture platforms and in vivo xenograft modelling, revealing that human AML disease specifically disrupts the adipocytic niche in BM. Leukaemic suppression of BM adipocytes led to imbalanced regulation of endogenous haematopoietic stem and progenitor cells, resulting in impaired myelo-erythroid maturation. In vivo administration of PPARγ agonists induced BM adipogenesis, which rescued healthy haematopoietic maturation while repressing leukaemic growth. Our study identifies a previously unappreciated axis between BM adipogenesis and normal myelo-erythroid maturation that is therapeutically accessible to improve symptoms of BM failure in AML via non-cell autonomous targeting of the niche.

Extracellular vesicles impose quiescence on residual hematopoietic stem cells in the leukemic niche

“…A series of studies over the past decade has shown that the presence of AML blasts in bone marrow leads to functional alterations in stromal components with emergence of a leukemia-permissive niche [15,27,[48][49][50]. Recently, investigators have also begun to provide detailed analyses of residual hematopoietic cells in the AML-BM, revealing the initially surprising, and seemingly selective, quiescence and preservation of LT-HSC [16,18,22,23,51].…”

“…Unlike the depletion of highly susceptible HSPC, HSC have proved to be more resilient during leukemic invasion, and multiple groups reported the relative accumulation of primitive hematopoietic cells in both murine models and xenograft studies [8,15,16,[21][22][23]. Unlike the depletion of highly susceptible HSPC, HSC have proved to be more resilient during leukemic invasion, and multiple groups reported the relative accumulation of primitive hematopoietic cells in both murine models and xenograft studies [8,15,16,[21][22][23].…”

Development, regulation, metabolism and function of bone marrow adipose tissues

“…Furthermore, cBMA number is modestly depleted by a prostaglandin E 2 receptor type 4 agonist in ovariectomized rats 25 . Although not measured in rodents, it appears likely that both rBMAT and cBMAT are reduced in response to profound starvation 54 , blood-letting 55 , leukemia 34 , and infection 56 . Thus, whilst the term “constitutive” as a descriptor of some BMAT depots has merit, there are also caveats that diminish its dogmatic applicability.…”

“…For instance, three weeks of cold exposure stimulates a dramatic and specific decrease in size and number of rBMAs in proximal tibia 21 . Other specific negative regulators of rBMA size or morphology include fasting 30 , intracerebral 31 or subcutaneous 32 leptin, intraperitoneal β 3 -agonist 33 , acute myeloid leukaemia 34 , exercise 35 and lactation 36 , some of which will be discussed in detail later within this review. Although development of rBMAT is independent of the lipodystrophy gene caveolin-1 ( Cav1 ), accumulation of rBMAs in proximal tibia is largely dependent on expression of another lipodystropy gene, cavin-1( Ptrf ) 21 .…”

“…For example, in vitro co-culture of Lin − blood cells with adipocytes increased numbers of hematopoietic progenitors and development of mature granulocytes 34 . Furthermore, in the context of leukemia, regeneration of healthy erythroid progenitors and granulocytes after irradiation was improved in mice in which BMAT was expanded by treatment with a PPARγ-agonist 34 . Importantly, the specific secretion of stem cell factor by BMAs, but not white adipocytes, is required in caudal vertebrae for maintenance of hematopoietic cells 68 .…”