Loss of Ikaros DNA-binding function confers integrin-dependent survival on pre-B cells and progression to acute lymphoblastic leukemia.
Loss of Ikaros DNA-binding function confers integrin-dependent survival on pre-B cells and progression to acute lymphoblastic leukemia.
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Ikaros (Ikzf1) dna结合域的缺失会产生显性阴性亚型，干扰Ikaros家族活性，并与人类前体B细胞急性淋巴细胞白血病（B- all）的不良预后相关。在这里，我们发现早期前b细胞中Ikaros DNA结合域的条件失活阻止了它们的分化，在这个阶段，整合素依赖的生态位粘附增强了丝裂原激活的蛋白激酶信号传导、增殖和自我更新，并减弱了前b细胞受体信号传导和分化。移植多克隆Ikzf1突变前b细胞导致长潜伏期寡克隆前b - all，表明Ikaros缺失有助于多步骤b -白血病的发生。这些结果解释了正常的前b细胞如何从高度增殖和基质依赖过渡到基质独立阶段，从而实现分化，为IKZF1突变型B-ALL提供了潜在的治疗策略。
Deletion of the Ikaros (Ikzf1) DNA-binding domain generates dominant-negative isoforms that interfere with Ikaros family activity and correlate with poor prognosis in human precursor B cell acute lymphoblastic leukemias (B-ALL). Here, we show that conditional inactivation of the Ikaros DNA binding domain in early pre-B cells arrests their differentiation at a stage where integrin-dependent niche adhesion augments mitogen-activated protein kinase signaling, proliferation, and self-renewal, and attenuates pre-B cell receptor signaling and differentiation. Transplantation of polyclonal Ikzf1 mutant pre-B cells results in long-latency oligoclonal pre-B-ALL, demonstrating that loss of Ikaros contributes to multistep B-leukemogenesis. These results explain how normal pre-B cells transit from a highly proliferative and stromal-dependent to a stromal-independent phase where differentiation is enabled, providing potential therapeutic strategies for IKZF1 mutant B-ALL.
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