Journal Article

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

Leber, Brian, Collins, Tony J., Ross, Catherine A., Allan, David S., Jackson, Michael F., Reid, Jennifer C., Campbell, Clinton J. V., Almakadi, Mohammed, Porras, Deanna P., Nakanishi, Mio, Benoit, Yannick D., Foley, Ronan, Bhatia, Mickie, Boyd, Allison L., Shapovalova, Zoya, Sabloff, Mitchell, Xenocostas, Anargyros, Salci, Kyle R., Aslostovar, Lili

2017

Overview

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. Boyd et al. monitored the effects of patient-derived acute myeloid leukaemia (AML) cells on human HSPCs in vivo and found that AML impairs bone marrow adipocyte differentiation, and this in turn impedes healthy endogenous haematopoiesis.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 631/532/1542 / 631/532/2118/2074 / 631/67 / 631/67/327 / Acute myeloid leukemia / Adipocytes / Adipocytes - pathology / Adipogenesis / Adipogenesis - physiology / Adult / Aged / Analysis / Anemia / Animals / Bone marrow / Bone Marrow - metabolism / Bone Marrow - pathology / Bone marrow cells / Bone Marrow Cells - metabolism / Bone Marrow Cells - pathology / Cancer Research / Cell Biology / Cell culture / Cells (biology) / Coculture Techniques - methods / Developmental Biology / Erythropoiesis / Erythropoiesis - physiology / Failure analysis / Female / Hematopoiesis / Hematopoietic Stem Cells / Humans / Leukemia / Leukemia, Myeloid, Acute - pathology / Life Sciences / Male / Maturation / Mice / Mice, Inbred NOD / Middle Aged / Patients / PPAR gamma - metabolism / Stem Cells / Stem Cells - pathology / Xenografts / Young Adult