Leukemic blasts program bone marrow adipocytes to generate a protumoral microenvironment

Manar S. Shafat, Thomas Oellerich, Sebastian Mohr, Stephen D. Robinson, Dylan R. Edwards, Christopher R. Marlein, Rachel E. Piddock, Matthew Fenech, Lyubov Zaitseva, Amina Abdul-Aziz, Jeremy Turner, Johnathan A. Watkins, Matthew Lawes, Kristian M. Bowles, Stuart A. Rushworth

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Despite currently available therapies most patients diagnosed with acute myeloid leukemia (AML) die of their disease. Tumor-host interactions are critical for the survival and proliferation of cancer cells; accordingly, we hypothesise that specific targeting of the tumor microenvironment may constitute an alternative or additional strategy to conventional tumor-directed chemotherapy. Since adipocytes have been shown to promote breast and prostate cancer proliferation, and because the bone marrow adipose tissue (MAT) accounts for up to 70% of bone marrow volume in adult humans, we examined the adipocyte-leukaemia cell interactions to determine if they are essential for the growth and survival of AML. Using in-vivo and in-vitro models of AML we show that bone marrow adipocytes from the tumor microenvironment support the survival and proliferation of malignant cells from patients with AML. We show that AML blasts alter metabolic processes in adipocytes to induce phosphorylation of hormone-sensitive lipase and consequently activate lipolysis, which then enables the transfer of fatty acids from adipocytes to AML blasts. In addition, we report that fatty acid binding protein-4 (FABP4) mRNA is up-regulated in adipocytes and AML when in co-culture. FABP4 inhibition using FABP4 shRNA knockdown or a small molecule inhibitor prevents AML proliferation on adipocytes. Moreover, knockdown of FABP4 increases survival in Hoxa9/Meis1-driven AML model. Finally, knockdown of carnitine palmitoyltransferase IA (CPT1A) in an AML patient-derived xenograft model improves survival. Here we report the first description of AML programming bone marrow adipocytes to generate a pro-tumoral microenvironment.
Original languageEnglish
Pages (from-to)1320-1332
Number of pages13
Issue number10
Early online date3 Jan 2017
Publication statusPublished - 9 Mar 2017

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