Leukemic stem cells hijack lineage inappropriate signalling pathways to promote their growth
Leukemic stem cells hijack lineage inappropriate signalling pathways to promote their growth
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DOI：
10.1101/2023.03.10.532081
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发表时间：
2023-04
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通讯作者：
S. Kellaway;S. Potluri;P. Keane;H. Blair;P. Chin;A. Ptasinska;Alice Worker;L. Ames;Assunta Adamo;D. Coleman;Naeem Khan;Salam A. Assi;A. Krippner-Heidenreich;M. Raghavan;P. Cockerill;O. Heidenreich;C. Bonifer
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作者：
S. Kellaway;S. Potluri;P. Keane;H. Blair;P. Chin;A. Ptasinska;Alice Worker;L. Ames;Assunta Adamo;D. Coleman;Naeem Khan;Salam A. Assi;A. Krippner-Heidenreich;M. Raghavan;P. Cockerill;O. Heidenreich;C. Bonifer
急性髓细胞白血病（AML）是由髓细胞生长和分化失调的多种突变引起的。细胞采用不同的基因调控网络特异性的个体突变，维持一个快速增殖的胚细胞群体，致命的后果，如果不治疗的病人。最常见的治疗选择仍然是针对这些细胞的化疗。然而，患者体内有一群静止的白血病干细胞（LSCs），它们可以从静止状态中出现，在治疗后引发复发。允许这些细胞再生的过程尚不清楚。在这里，我们研究了表征良好的t(8;21) AML亚型作为解决这个问题的模型。使用一种新的t（8;21）患者来源的异种移植模型，我们发现t(8;21) LSCs异常激活VEGF和IL-5信号通路。这两种途径都在一个由驱动癌蛋白RUNX1::ETO和AP-1/GATA2轴组成的调控回路中运作，允许LSCs在保持自我更新能力的同时重新进入细胞周期。
Acute Myeloid Leukemia (AML) is caused by multiple mutations which dysregulate growth and differentiation of myeloid cells. Cells adopt different gene regulatory networks specific to individual mutations, maintaining a rapidly proliferating blast cell population with fatal consequences for the patient if not treated. The most common treatment option is still chemotherapy which targets such cells. However, patients harbour a population of quiescent leukemic stem cells (LSCs) which can emerge from quiescence to trigger relapse after therapy. The processes that allow such cells to re- grow remain unknown. Here, we examined the well characterised t(8;21) AML sub-type as a model to address this question. Using a novel t(8;21) patient-derived xenograft model, we show that t(8;21) LSCs aberrantly activate the VEGF and IL-5 signalling pathways. Both pathways operate within a regulatory circuit consisting of the driver oncoprotein RUNX1::ETO and an AP-1/GATA2 axis allowing LSCs to re-enter the cell cycle while preserving self-renewal capacity.