BIRC5 upregulation enhances DNMT3A-mutant T-ALL cell survival and pathogenesis

Blood Neoplasia Pub Date : 2024-09-05 DOI:10.1016/j.bneo.2024.100040

Wangisa Dunuwille , William C. Wilson , Hassan Bjeije , Nancy Issa , Wentao Han , Tyler M. Parsons , Andrew L. Young , Infencia Xavier Raj , Aishwarya Krishnan , Tarang Gaur , Eunice S. Wang , Andrew P. Weng , Matthew C. Stubbs , Hamza Celik , Amanda F. Cashen , John R. Edwards , Grant A. Challen

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Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic neoplasm. Although the prognosis of pediatric T-ALL has improved with intensified chemotherapy regimens, this benefit has largely not translated to the adult T-ALL population. Development of new treatments requires understanding the mechanisms driven by specific mutations. DNMT3A mutations are identified in ∼10% to 18% of adult patients with T-ALL and are associated with poor clinical outcomes. Here, using primary human specimens, we show that cells from patients with T-ALL with DNMT3A mutations are resistant to apoptosis and certain chemotherapies. Elevated JAK/STAT signaling drove prosurvival programs in patients with mutant DNMT3A, and JAK/STAT inhibition restored sensitivity to chemotherapy. The prosurvival gene BIRC5 was upregulated in patients with DNMT3A-mutant T-ALL, and these cells were specifically sensitive to the Baculoviral IAP Repeat Containing 5 (BIRC5) inhibitor YM155. Genetic inhibition of BIRC5 in vivo lead to rapid depletion of DNMT3A-mutant T-ALL cells in patient-derived xenografts, positioning BIRC5 as a precision medicine target for these patients.

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BIRC5 上调可提高 DNMT3A 突变 T-ALL 细胞的存活率和发病率

摘要T细胞急性淋巴细胞白血病（T-ALL）是一种侵袭性造血肿瘤。虽然小儿 T-ALL 的预后随着化疗方案的加强而有所改善，但这种益处在很大程度上并没有转化到成人 T-ALL 群体中。开发新的治疗方法需要了解特定突变的驱动机制。在10%到18%的成人T-ALL患者中发现了DNMT3A突变，而且与不良的临床预后有关。在这里，我们利用原代人类标本表明，来自T-ALL患者的细胞如果存在DNMT3A突变，就会对细胞凋亡和某些化疗产生耐药性。JAK/STAT信号的升高推动了DNMT3A突变患者的促生存程序，抑制JAK/STAT可恢复对化疗的敏感性。在DNMT3A突变的T-ALL患者中，前生存基因BIRC5上调，这些细胞对含有IAP重复序列5的杆状病毒（Baculoviral IAP Repeat Containing 5，BIRC5）抑制剂YM155特别敏感。在体内对BIRC5进行基因抑制可迅速清除患者异种移植中的DNMT3A突变T-ALL细胞，从而将BIRC5定位为这些患者的精准医疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Blood Neoplasia

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