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October 17, 2017

Leukemia May Shrivel If Fat Cells in Marrow Are Plumped

Bolstering adipogenesis in the bone marrow niche may curb leukemia, not by killing leukemic cells directly, but by adjusting the bone marrow environment to favor the maturation of healthy blood cells. The image on the left shows fat cells (white circles) in healthy human bone marrow; the image on the right, bone marrow in a patient with leukemia. [McMaster University]

  • Bolstered by an adipogenesis-promoting drug, fat cells in the bone marrow effectively “crowded out” leukemia, yet they made room for healthy blood cells. Such effects are not simply due to physical crowding in the bone marrow niche. They are more about cells cramping each other’s styles while they try to attain their fully differentiated forms.

    Altering the bone marrow environment so that it favors the formation of healthy blood cells and disfavors the formation of leukemic cells could present an indirect way to treat acute myeloid leukemia (AML). Indirect treatment options would be welcome given that conventional treatments, which try to kill diseased cells directly, haven’t brought dramatic improvements to the standard-of-care in recent decades.

    The possibility of indirect treatments emerged from research conducted by scientists based at McMaster University.

    "The focus of chemotherapy and existing standard-of-care is on killing cancer cells,” said Mick Bhatia, Ph.D., director and senior scientist at the McMaster University’s Stem Cell and Cancer Research Institute. “Instead, we took a completely different approach—changing the environment the cancer cells live in. This not only suppressed the ‘bad’ cancer cells, but also bolstered the ‘good’ healthy cells allowing them to regenerate in the new drug-induced environment."

    Bhatia is the senior author of a study that appeared October 16 in the journal Nature Cell Biology. The study, entitled “Acute Myeloid Leukaemia Disrupts Endogenous Myelo-Erythropoiesis by Compromising the Adipocyte Bone Marrow Niche,” identified a previously unappreciated axis between bone marrow adipogenesis and normal myelo-erythroid maturation. Moreover, the study found that the axis is therapeutically accessible to improve symptoms of bone marrow failure in AML via non–cell autonomous targeting of the niche.

    The McMaster-led study was conducted over the past three and half years and started from observations of leukemia patients. This led to the collection of bone marrow samples from larger cohorts of patients with the Ottawa Hospital Research Institute, as well as those from Western University and Hamilton Health Sciences, for the next steps of investigation. This included detailed study and imaging of individual leukemia cells compared to healthy cells residing in the bone marrow (BM), which revealed the effects of targeting fat cells.

    “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,” wrote the authors of the Nature Cell Biology article. “Leukaemic suppression of BM adipocytes led to imbalanced regulation of endogenous haematopoietic stem and progenitor cells, resulting in impaired myelo-erythroid maturation.”

    The article also indicated that a drug commonly used to moderate diabetes that induces fat cell production in the bone marrow was used and was found to help foster red blood cell production as well as suppress leukemic disease: “In vivo administration of PPARγ [peroxisome proliferator-activated receptor gamma] agonists induced BM adipogenesis, which rescued healthy haematopoietic maturation while repressing leukaemic growth.”

    The production of healthy red blood cells is critical for those with AML, but is sometimes overlooked as conventional treatments focus on killing the leukemia cells alone. Patients with this disease suffer from anemia and infection due to the failure of healthy blood production, all of which are leading causes of hospitalization and death from the disease.

    "Our approach represents a different way of looking at leukemia and considers the entire bone marrow as an ecosystem, rather than the traditional approach of studying and trying to directly kill the diseased cells themselves," said Allison Boyd, Ph.D., postdoctoral fellow with the research institute and first author of the study.

    "These traditional approaches have not delivered enough new therapeutic options for patients. The standard-of-care for this disease hasn't changed in several decades."

    "The fact that we can target one cell type in one tissue using an existing drug makes us excited about the possibilities of testing this in patients," emphasized Bhatia. "We can envision this becoming a potential new therapeutic approach that can either be added to existing treatments or even replace others in the near future. The fact that this drug activates blood regeneration may provide benefits for those waiting for bone marrow transplants by activating their own healthy cells."

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