Acute myeloid leukemia induces protumoral p16INK4a-driven senescence in the bone marrow microenvironment
Acute myeloid leukemia induces protumoral p16INK4a-driven senescence in the bone marrow microenvironment
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DOI：
10.1182/blood-2018-04-845420
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发表时间：
2019-01-31
期刊：
影响因子：
20.3
通讯作者：
Rushworth, Stuart A.
中科院分区：
文献类型：
--
作者：
Abdul-Aziz, Amina M.;Sun, Yu;Rushworth, Stuart A.
急性髓性白血病（AML）是一种高度依赖于骨髓（BM）微环境的年龄相关性疾病。随着年龄的增长，组织积累衰老细胞，其特征在于细胞增殖的不可逆停滞和一组促炎细胞因子、趋化因子和生长因子的分泌，统称为衰老相关分泌表型（SASP）。在这里，我们报告说，AML母细胞诱导骨髓微环境内的基质细胞衰老表型，骨髓基质细胞衰老是由p16 INK 4a表达驱动。表达p16 INK 4a的衰老基质细胞然后通过SASP反馈以促进AML原始细胞存活和增殖。重要的是，在体内选择性消除p16 INK 4a 1衰老BM基质细胞改善了白血病小鼠的存活率。接下来，我们发现白血病驱动的衰老肿瘤微环境是由AML诱导的NOX 2衍生的超氧化物引起的。最后，使用p16- 3 MR小鼠模型，我们表明通过靶向NOX 2，我们减少了BM基质细胞衰老，从而减少了AML增殖。总之，这些数据确定了白血病产生的NOX 2衍生的超氧化物作为BM基质细胞中肿瘤前p16 INK 4a依赖性衰老的驱动因素。我们的研究结果揭示了衰老微环境对白血病病理生理的重要性。这些数据现在为研究专门针对围绕和支持AML的“良性”衰老细胞的药物打开了大门。
Acute myeloid leukemia (AML) is an age-related disease that is highly dependent on the bone marrow (BM) microenvironment. With increasing age, tissues accumulate senescent cells, characterized by an irreversible arrest of cell proliferation and the secretion of a set of proinflammatory cytokines, chemokines, and growth factors, collectively known as the senescence-associated secretory phenotype (SASP). Here, we report that AML blasts induce a senescent phenotype in the stromal cells within the BM microenvironment and that the BM stromal cell senescence is driven by p16INK4a expression. The p16INK4a-expressing senescent stromal cells then feed back to promote AML blast survival and proliferation via the SASP. Importantly, selective elimination of p16INK4a1 senescent BM stromal cells in vivo improved the survival of mice with leukemia. Next, we find that the leukemia-driven senescent tumor microenvironment is caused by AML-induced NOX2-derived superoxide. Finally, using the p16-3MR mouse model, we show that by targeting NOX2 we reduced BM stromal cell senescence and consequently reduced AML proliferation. Together, these data identify leukemia-generated NOX2-derived superoxide as a driver of protumoral p16INK4a-dependent senescence in BM stromal cells. Our findings reveal the importance of a senescent microenvironment for the pathophysiology of leukemia. These data now open the door to investigate drugs that specifically target the "benign" senescent cells that surround and support AML.