Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Medical Scientist Training Program, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Leukemia. 2024 May;38(5):951-962. doi: 10.1038/s41375-024-02232-8. Epub 2024 Mar 29.
Relapse in T-cell acute lymphoblastic leukemia (T-ALL) may signify the persistence of leukemia-initiating cells (L-ICs). Ectopic TAL1/LMO expression defines the largest subset of T-ALL, but its role in leukemic transformation and its impact on relapse-driving L-ICs remain poorly understood. In TAL1/LMO mouse models, double negative-3 (DN3; CD4CD8CD25CD44) thymic progenitors harbored L-ICs. However, only a subset of DN3 leukemic cells exhibited L-IC activity, and studies linking L-ICs and chemotolerance are needed. To investigate L-IC heterogeneity, we used mouse models and applied single-cell RNA-sequencing and nucleosome labeling techniques in vivo. We identified a DN3 subpopulation with a cell cycle-restricted profile and heightened TAL1/LMO2 activity, that expressed genes associated with stemness and quiescence. This dormant DN3 subset progressively expanded throughout leukemogenesis, displaying intrinsic chemotolerance and enrichment in genes linked to minimal residual disease. Examination of TAL/LMO patient samples revealed a similar pattern in CD7CD1a thymic progenitors, previously recognized for their L-IC activity, demonstrating cell cycle restriction and chemotolerance. Our findings substantiate the emergence of dormant, chemotolerant L-ICs during leukemogenesis, and demonstrate that Tal1 and Lmo2 cooperate to promote DN3 quiescence during the transformation process. This study provides a deeper understanding of TAL1/LMO-induced T-ALL and its clinical implications in therapy failure.
T 细胞急性淋巴细胞白血病 (T-ALL) 的复发可能表明白血病起始细胞 (L-ICs) 的持续存在。异位 TAL1/LMO 表达定义了 T-ALL 的最大亚群，但它在白血病转化中的作用及其对驱动复发的 L-ICs 的影响仍知之甚少。在 TAL1/LMO 小鼠模型中，双阴性-3 (DN3; CD4CD8CD25CD44) 胸腺祖细胞含有 L-ICs。然而，只有一小部分 DN3 白血病细胞表现出 L-IC 活性，需要进行将 L-ICs 与趋化耐受联系起来的研究。为了研究 L-IC 的异质性，我们使用了小鼠模型，并在体内应用了单细胞 RNA 测序和核小体标记技术。我们鉴定了一个具有细胞周期受限特征和 TAL1/LMO2 活性增强的 DN3 亚群，该亚群表达与干性和静止相关的基因。这种休眠的 DN3 亚群在整个白血病发生过程中逐渐扩大，表现出内在的趋化耐受和与微小残留疾病相关基因的富集。对 TAL/LMO 患者样本的检查揭示了 CD7CD1a 胸腺祖细胞中存在类似的模式，先前已被认为具有 L-IC 活性，表现出细胞周期受限和趋化耐受。我们的研究结果证实了休眠的、趋化耐受的 L-ICs 在白血病发生过程中的出现，并表明 Tal1 和 Lmo2 合作在转化过程中促进 DN3 的静止。这项研究提供了对 TAL1/LMO 诱导的 T-ALL 的更深入理解及其在治疗失败中的临床意义。
