Department of Molecular Haematology, Norwich Medical School, The University of East Anglia, Norwich Research Park, Norwich, United Kingdom.
Department of Medicine II, Hematology/Oncology, Goethe University, Frankfurt, Germany.
Blood. 2017 Mar 9;129(10):1320-1332. doi: 10.1182/blood-2016-08-734798. Epub 2017 Jan 3.
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 hypothesize that specific targeting of the tumor microenvironment may constitute an alternative or additional strategy to conventional tumor-directed chemotherapy. Because adipocytes have been shown to promote breast and prostate cancer proliferation, and because the bone marrow adipose tissue accounts for up to 70% of bone marrow volume in adult humans, we examined the adipocyte-leukemia 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) messenger RNA is upregulated in adipocytes and AML when in coculture. FABP4 inhibition using FABP4 short hairpin RNA 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 in an AML patient-derived xenograft model improves survival. Here, we report the first description of AML programming bone marrow adipocytes to generate a protumoral microenvironment.
尽管目前有多种治疗方法，但大多数被诊断患有急性髓细胞白血病（AML）的患者仍死于该病。肿瘤-宿主相互作用对癌细胞的存活和增殖至关重要；因此，我们假设特异性靶向肿瘤微环境可能构成传统肿瘤导向化疗的替代或附加策略。因为已经表明脂肪细胞促进乳腺癌和前列腺癌的增殖，并且骨髓脂肪组织占成年人体内骨髓体积的高达 70%，所以我们检查了脂肪细胞-白血病细胞相互作用，以确定它们是否对 AML 的生长和存活至关重要。使用 AML 的体内和体外模型，我们表明来自肿瘤微环境的骨髓脂肪细胞支持 AML 患者的恶性细胞的存活和增殖。我们表明 AML blasts 通过改变脂肪细胞中的代谢过程来诱导激素敏感脂肪酶的磷酸化，从而激活脂肪分解，从而使脂肪酸从脂肪细胞转移到 AML blasts。此外，我们报告了当共培养时，脂肪细胞和 AML 中的脂肪酸结合蛋白-4（FABP4）信使 RNA 上调。使用 FABP4 短发夹 RNA 敲低或小分子抑制剂抑制 FABP4 可防止 AML 在脂肪细胞上增殖。此外，FABP4 的敲低增加了 Hoxa9/Meis1 驱动的 AML 模型中的存活。最后，在 AML 患者衍生的异种移植模型中敲低肉毒碱棕榈酰转移酶 IA 可提高存活率。在这里，我们首次描述了 AML 编程骨髓脂肪细胞以产生促肿瘤微环境。
