PO.ET02.10 · 实验与分子治疗

JAK抑制联合阿糖胞苷在急性巨核细胞白血病中的协同抗白血病活性

Synergistic antileukemic activity of JAK inhibition combined with cytarabine in acute megakaryoblastic leukemia

编号 4467 展板 15 时间 4/21 09:00–12:00 区域 Section 13 主讲 Akira Shimada, MD;PhD

分会场 Drug Combinations, Repurposing, and Differentiation

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作者与单位 Authors & Affiliations

Akira Shimada¹, Shiho Aoki¹, Hiroko Hayakawa², Erico Jimbo³, Narumi Omika³, Kaito Furuya³, Hideya Asai³, Hiroki Yoshinari³, Hitomi Niijima³, Yuta Kawahara³, Kentaro Ushijima⁴, Masakazu Mimaki⁵, Mitsuteru Hiwatari⁵

¹Jichi Medical University, Tochigi, Japan,²Research Equipment Center, Jichi Medical University, Tochigi, Japan,³Pediatrics, Jichi Medical University, Tochigi, Japan,⁴Faculty of Pharmaceutical Sciences, Yamaguchi University of Science, Yamaguchi, Japan,⁵Pediatrics, Teikyo University, Tokyo, Japan

摘要 Abstract

中文摘要

背景：急性巨核细胞白血病（AMKL）仍是治疗难题，对标准的以阿糖胞苷为基础的方案反应有限，且常发生微环境介导的耐药。JAK-STAT信号通路的异常激活被认为与AMKL发病机制有关，但尚未在与阿糖胞苷联合治疗中得到充分利用。方法：我们在多个临床前模型中评估了JAK抑制剂联合阿糖胞苷的抗白血病疗效：(i) AMKL细胞系（包括CMK、CMY、MKPL1、UT7、MOLM16、Mo7e），评估活力、凋亡和联合指数；(ii) 与间充质细胞（MSC）的三维（3D）共培养，模拟骨髓龛介导的保护；以及(iii) AMKL小鼠异种移植模型，评估白血病负荷和生存。结果：在细胞系实验中，JAK抑制剂加阿糖胞苷显示出显著协同作用（联合指数 < 0.7），相比任一单药凋亡（Annexin V+）显著增加、增殖降低。在3D MSC共培养模型中，微环境保护AMKL细胞免于阿糖胞苷诱导的死亡，但这种保护作用被JAK抑制所消除，恢复了阿糖胞苷敏感性，尤其在MOLM16和MKPL1细胞中。体内实验中，联合治疗相比单用阿糖胞苷显著降低白血病负荷（p < 0.05）并显著延长中位生存期。在机制上，ruxolitinib抑制STAT3和STAT5的磷酸化，并与阿糖胞苷联合发挥协同效应；然而，这种对磷酸化的抑制效应在3D共培养条件下减弱。结论：我们的结果提供了有力的临床前证据，表明JAK抑制联合阿糖胞苷在AMKL中产生协同抗白血病效应，包括在龛保护环境中，并显著改善体内结局。这些数据有力地支持了在AMKL患者、尤其是那些具有JAK-STAT通路激活的患者中进行该联合方案临床评估的理论依据。

查看英文原文 English abstract

Background: Acute megakaryoblastic leukemia (AMKL) remains a therapeutic challenge, with limited responsiveness to standard cytarabine-based regimens and frequent microenvironment-mediated resistance. Aberrant activation of the JAK-STAT signaling pathway has been implicated in AMKL pathogenesis but has not been fully exploited therapeutically in combination with cytarabine. Methods: We evaluated the antileukemic efficacy of combining a JAK inhibitor with cytarabine across multiple preclinical models: (i) AMKL cell lines (including CMK, CMY, MKPL1, UT7, MOLM16, Mo7e) assessing viability, apoptosis, and combination index; (ii) three-dimensional (3D) co-culture with mesenchymal cells (MSCs) modelling bone-marrow niche-mediated protection; and (iii) murine xenograft models of AMKL assessing leukemic burden and survival. Results: In cell-line experiments, the JAK inhibitor plus cytarabine demonstrated marked synergy (combination index < 0.7) with significantly increased apoptosis (Annexin V+) and reduced proliferation compared to either agent alone. In the 3D MSC co-culture model, the microenvironment protected AMKL cells from cytarabine-induced death, but this protective effect was abrogated by JAK inhibition, restoring cytarabine sensitivity especially in MOLM16 and MKPL1 cells. In vivo, combination therapy significantly reduced leukemic burden (p < 0.05) and significantly prolonged median survival compared to cytarabine alone. Mechanistically, ruxolitinib suppressed phosphorylation of STAT3 and STAT5 and exerted a synergistic effect in combination with cytarabine; however, this inhibitory effect on phosphorylation was attenuated under the 3D co-culture condition. Conclusions: Our results provide robust preclinical evidence that combining JAK inhibition with cytarabine yields synergistic antileukemic effects in AMKL, including in a niche-protected context, and significantly improves in vivo outcomes. This data strongly supports the rationale for clinical evaluation of this combination in AMKL patients, especially those with JAK-STAT pathway activation.

利益披露 Disclosure

A. Shimada, None.. S. Aoki, None.. H. Hayakawa, None.. E. Jimbo, None.. N. Omika, None.. K. Furuya, None.. H. Asai, None.. H. Yoshinari, None.. H. Niijima, None.. Y. Kawahara, None.. K. Ushijima, None.. M. Mimaki, None.. M. Hiwatari, None.

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