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.
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This work was supported by a research grant to M.B. from the Marta and Owen Boris Foundation and Canadian Cancer Society Research Institute. A.L.B. was supported by graduate research scholarships: Ontario Graduate Scholarship, National Science and Engineering Research Council (NSERC) and the Jans Graduate Scholarship in Stem Cell Research. J.C.R. was supported by a doctoral scholarship from the Canadian Institute of Health Research (CIHR) and K.R.S. was supported by the NSERC Create M3 program. Y.D.B. was funded by the Quebec Health Research Funds (FRQS) and CIHR, and holds a fellowship from the Cancer Research Society (CRS). M.B. is a Canada Research Chair in Stem Cell Biology and Regenerative Medicine. We acknowledge M. Graham for human sample processing, as well as A. Fiebig-Comyn, W. Whittaker, L. Robson and A. Scott for assistance with animal husbandry and in vivo experiments. We thank L. May, M. J. Smith and M. Bruni for assistance with histology and immunofluorescence staining. We also thank C. Magruder and C. Hopkins for illustrative images.
The authors declare no competing financial interests.
Integrated supplementary information
Supplementary Figure 1 Healthy human myelo-erythroid cells are reproducibly suppressed by AML co-transplantation.
(a–g) Experimental design (a), representative FACS plots (b,d,f) and quantification (c,e,g) of human populations in xenograft BM following healthy human HSPC transplantation alone or together with human AML. Data points represent group averages from n = 5 (e) or n = 6 (c,g) independent experiments. (h) Absolute BM cell number recovered by mechanical dissociation. Data points represent independent xenografted mice from 2 experiments (precise n values indicated in the figure). Findings are representative of 6 experiments. (i–l) Experimental design (i), representative FACS plots (j) and quantification (k,l) of healthy human CD45+CD33+ populations in xenograft BM following healthy human HSPC transplantation alone or together with human AML. (k) n = 37 (alone) and n = 35 (with AML) independent xenografted mice pooled from 6 experiments. (l) Data points represent group averages from n = 6 independent experiments. (m–o) Experimental design (m) to compare competitive BM repopulation between HSPCs from two healthy human donors (analyzed in n,o). Constant cell doses from human Donor A were competitively transplanted against escalating doses of competitor cells from human Donor B. (n,o) FACS quantification of overall chimerism (n) and myeloid/lymphoid cell frequencies (o) specific to healthy human Donor A. Data represent n = 5 (low dose) and n = 4 (high dose) independent xenografted mice from 1 experiment, and reproduced in 3 additional experiments. (p–s) Experimental design (p), representative FACS plots (q) and quantification (r,s) of healthy human CD45+CD34+ populations in xenograft BM following healthy human HSPC transplantation alone or together with human AML. (r) n = 34 (alone) and n = 32 (with AML) independent xenografted mice pooled from 6 experiments. (s) Data points represent group averages from n = 6 independent experiments. All FACS plots are representative of at least 5 independent experiments; blue coloring indicates healthy human cells, red indicates human AML cells, and grey indicates residual mouse BM cells. Quantification was based on patient and donor-specific HLA-A2 gating. Numbers within data points indicate AML Patient IDs. All data are means ± s.e.m. Statistical significance was assessed by Fisher’s Exact test (c), paired t-tests (e,g,l,s), unpaired t-tests (h,n,o), or Mann–Whitney U tests (k,r). Source data can be found in Supplementary Table 8.
(a) Absolute PLN+ adipocyte counts and DAPI+ nucleated cell counts per xenograft femur section. n = 9 (healthy) and n = 8 (AML) pooled from 5 experiments (values correspond to frequencies reported in Fig. 2h). (b) Representative images of xenograft femur sections showing that AML engraftment reduces the number of adipocytes per unit area, whereas nucleated cell counts remain stable. Scale bar, 70 μm. (c) Body weights as a function of human leukemic burden in BM. Values reflect n = 7, 2, 7, 7 independent xenografted mice (healthy human chimerism, 20% AML, 20–80% AML, and >80% AML) pooled from 3 experiments (1 healthy sample, AML Patients #2 and #6). (d,e) Nonfasted serum glucose levels in mice reconstituted with healthy human hematopoieisis or human AML (Patient #1). n = 5 biologically independent xenografted mice/group from 1 experiment (1 mouse with <20% AML, 3 mice with 20–80% AML, and 1 mouse with >80% AML). (f) Representative immunofluorescence images of inguinal fat pad tissue collected from mice engrafted with human AML (Patient #2) or matched non-transplanted controls. PLN, perilipin. Low magnification images (left) represent full tissue montage images of up to 347 fields (scale bar, 1.3 mm), while high magnification images (right), represent individual fields (scale bar, 70 μm). BM leukemic chimerism was >90%. (g,h) Adipocyte number (g) and cross-sectional area measurements (h) from fat pad sections shown in f. Area measurements reflect n = 73422 (control) and n = 46242 (AML) independent adipocytes from individual tissue sections. Analysis is representative of 3 independent mice/group from separate experiments. All data are means ± s.e.m. Statistical significance was assessed by unpaired t-tests (a,d), Kruskal–Wallis test (c), or Mann–Whitney U test (h). No statistical analyses were performed in e. Source data can be found in Supplementary Table 8.
Supplementary Figure 3 Osteoblasts and yellow marrow adipocytes persist in BM despite substantial levels of leukemic disease.
(a) Representative PLN immunofluorescence images of femur sections from AML-engrafted mice or non-transplanted controls, corresponding to high magnification images shown in Fig. 3e. Scale bar, 250 μm. (b,c) PLN quantification of absolute adipocyte numbers in tail vertebrae sections. N numbers (and data points) represent independent xenografted mice from 2 experiments (precise n values indicated in the figure). Data values for Patient #2 correspond to frequencies shown in Fig. 3g. (d) High magnification images of H&E-stained mouse femurs engrafted with healthy human hematopoietic cells or human AML (Patient #2). Chimerism levels are similar between healthy and AML grafts (>90% human chimerism). Yellow arrowheads indicate osteoblasts. Scale bar, 20 μm. (e) Immunofluorescence quantification of Osx + osteoblasts in femur sections from AML-engrafted mice (Patient #6) or healthy human HSPC-engrafted mice. n = 2 mice (healthy) and n = 4 mice (AML) from 1 experiment. This was reproduced in an additional experiment using an independent AML patient sample (Fig. 3k). (f–h) MicroCT quantification of mineralized bone; additional parameters corresponding to data shown in Fig. 3l–n (AML-xenografts from Patient #2). n = 3 biologically independent mice/group from 1 experiment. All data are means ± s.e.m. Statistical significance was assessed by Mann–Whitney U test (b) or unpaired t-tests (c,f–h). No statistical analyses were performed in e. Source data can be found in Supplementary Table 8.
Supplementary Figure 4 Characterization of MSCs and hematopoietic repopulating cells isolated from BM aspirates of healthy human donors or AML patients.
(a, b) Phase contrast images and FACS plots of MSCs isolated from the BM of healthy adult donors (a) and AML patients (b). Scale bars, 100 μm. (c) FACS analysis of human hematopoietic repopulation in the BM of mice transplanted with 10 × 106 BM mononuclear cells from AML Patients #12 or #13. Plots are representative of n = 4 (Patient#12), and n = 2 (Patient#13) independent xenografted mice, with similar results. (d,e) Heatmap (d) and bar graphs (e) showing the frequency of mature BODIPY+ adipocytes differentiated from healthy human BM-MSCs that were cultured in different cocktails of adipogenesis-inducing agents (variable concentrations of dexamethasone, IBMX, and insulin, together with a constant concentration of 2% FBS across all conditions). Each cocktail was tested in the presence or absence of 10 ng ml−1 IL-6 as a known inhibitor of adipogenesis59. Dashed lines indicate the final cocktail selected, based on the greatest sensitivity to detect inhibitory effects of IL-6. (d) Each heatmap value represents the average of two replicate wells. (e) Only values from 500 μM IBMX conditions are plotted. Source data can be found in Supplementary Table 8.
Supplementary Figure 5 In vivo GW1929 treatment expands adipose tissue and promotes healthy myelo-erythropoiesis.
(a) Schematic showing 4-day Transwell co-culture of healthy human Lin− cells with healthy human BM-MSCs or differentiated human adipocytes (analysis in b,c). (b) FACS quantification of CD15+ granulocyte-lineage cells. Data represent group averages from n = 3 biologically independent experiments. (c) Quantification of human erythroid progenitors using methylcellulose CFU assays. n = 7 (MSCs) and n = 14 (adipocytes) independently assayed wells, pooled from 3 experiments. (d) Heatmap of probe sets most preferentially expressed in mature human osteoblasts versus adipocytes (GSE945129). (e) Normalized PPARγ transcript expression levels in mature human osteoblasts versus adipocytes (n = 3 biologically independent samples/group, GSE945129). (f) Experimental design to validate in vivo GW1929 dosing in non-transplanted mice (analysis in g–k; all n = 5 (vehicle) and n = 4 (GW1929) independent mice from 1 experiment). (g,h) Effects of GW1929 treatment on previously reported39 PPARγ-sensitive parameters of fat mass (g) and non-fasted serum glucose (h). (i–k) Whole femur dot plots (i) and image-based quantification of BM adipocyte frequency (j) and size (k). PLN, perilipin. (l) Experimental design to evaluate effects of in vivo GW1929 treatment on BM adipocytes and healthy human myelo-erythroid cells (analysis in m,n). (m,n) Correlation of BM adipocyte frequencies versus human erythroid colony number (m) or FACS-quantified healthy human CD45+CD15+ granulocytes (n). Data points represent n = 9 independently assayed wells (m) or n = 7 independent xenografted mice (n) from 1 experiment. Findings were reproduced in 3 additional experiments with independent healthy human cells (Fig. 6e, g). (o) Schematic showing 4-day in vitro culture of healthy human Lin− cells in 0.1% DMSO (vehicle) or 20 μM GW1929 (analysis in p,q). (p) FACS quantification of CD15+ granulocyte-lineage cells. Data represent group averages from n = 6 biologically independent experiments. (q) Quantification of human erythroid progenitors using methylcellulose CFU assays. Data points represent n = 6 independently assayed wells/group, pooled from 2 experiments. All data are means ± s.e.m. Statistical significance was assessed by paired t-tests (b,p), Mann–Whitney U tests (c,q), two-tailed unpaired t-test (e), one-tailed unpaired t-tests (g,h,j,k), or Pearson’s correlation (m,n). Source data can be found in Supplementary Table 8.
Supplementary Figure 6 Adipogenesis-promoting therapy limits leukemic progression in a non-cell autonomous manner.
(a,b) Schematic (a) and FACS/Trypan blue quantification (b) of leukemic blasts disseminated to the spleen from BM progenitors. Human AML-xenografts (Patient #2) were treated with corn oil (vehicle) or 10 mg kg−1 GW1929, as outlined in Fig. 5m. n = 3 (vehicle) and n = 4 (GW1929) independent xenografted mice from 1 experiment. (c) FACS quantification of human AML dissemination in the BM and spleens of xenografted mice (Patient #2). Data points represent individual mice analyzed at various time points post-engraftment, from 1 experiment that was performed independently from drug treatment experiments in panel b. Findings have been replicated in 2 additional experiments. (d) Western blots showing PPARγ protein levels in human AML cells versus healthy human BM-MSCs and in vitro-differentiated human adipocytes. Unprocessed blots can be found in Supplementary Fig. 7. Images are representative of 3 independent Western blots, each with similar results. (e,f) Viability (left) and leukemic progenitor frequency (right) following overnight culture of human AML cells with 0.1% DMSO (0 μM GW1929) or 5–20 μM GW1929. N numbers (and data points) represent independently assayed wells shown separately for 2 experiments (precise n values are indicated in the figure). All data are means ± s.e.m. Statistical significance was assessed by unpaired t-test (b) or one-way ANOVA with Newman–Keuls Multiple Comparison Test (e,f). Source data can be found in Supplementary Table 8.
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Boyd, A., Reid, J., Salci, K. et al. Acute myeloid leukaemia disrupts endogenous myelo-erythropoiesis by compromising the adipocyte bone marrow niche. Nat Cell Biol 19, 1336–1347 (2017). https://doi.org/10.1038/ncb3625
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