RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia
RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia
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DOI：
10.1172/jci141566
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发表时间：
2021-03-15
影响因子：
15.9
通讯作者：
Matlawska-Wasowska, Ksenia
中科院分区：
文献类型：
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作者：
Matthijssens, Filip;Sharma, Nitesh D.;Matlawska-Wasowska, Ksenia
T细胞急性淋巴细胞白血病（T-ALL）是一种侵袭性血液系统恶性肿瘤，与B细胞ALL相比预后较差。在这里，我们发现，Runt相关转录因子2（RUNX 2）在高危T-ALL与KMT 2A重排（KMT 2A-R）或不成熟的免疫表型上调。在KMT 2A-R细胞中，我们将RUNX 2鉴定为KMT 2A嵌合体的直接靶点，其中RUNX 2与KMT 2A启动子反向结合，建立了调节前馈机制。值得注意的是，RUNX 2是未成熟和KMT 2A-R T-ALL细胞在体外和体内存活所必需的。我们报告了RUNX 2对CXCR 4信号传导的直接转录调控，从而促进了趋化性、粘附性和向髓内和髓外位点的归巢。RUNX 2通过积极调节糖酵解和氧化磷酸化，增加T-ALL细胞的代谢活性，从而实现这些需要能量的过程。同时，RUNX 2上调增加了T-ALL细胞中的线粒体动力学和生物合成。最后，作为概念证明，我们证明了未成熟和KMT 2A-R T-ALL细胞容易受到RUNX 2及其辅因子CBF β之间相互作用的药理学靶向作用的影响。总之，我们表明，RUNX 2作为一个依赖性因素，在高风险亚型的人T-ALL通过伴随调节肿瘤代谢和白血病细胞迁移。
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with inferior outcome compared with that of B cell ALL. Here, we show that Runt-related transcription factor 2 (RUNX2) was upregulated in high-risk T-ALL with KMT2A rearrangements (KMT2A-R) or an immature immunophenotype. In KMT2A-R cells, we identified RUNX2 as a direct target of the KMT2A chimeras, where it reciprocally bound the KMT2A promoter, establishing a regulatory feed-forward mechanism. Notably, RUNX2 was required for survival of immature and KMT2A-R T-ALL cells in vitro and in vivo. We report direct transcriptional regulation of CXCR4 signaling by RUNX2, thereby promoting chemotaxis, adhesion, and homing to medullary and extramedullary sites. RUNX2 enabled these energy-demanding processes by increasing metabolic activity in T-ALL cells through positive regulation of both glycolysis and oxidative phosphorylation. Concurrently, RUNX2 upregulation increased mitochondrial dynamics and biogenesis in T-ALL cells. Finally, as a proof of concept, we demonstrate that immature and KMT2A-R T-ALL cells were vulnerable to pharmacological targeting of the interaction between RUNX2 and its cofactor CBF beta. In conclusion, we show that RUNX2 acts as a dependency factor in high-risk subtypes of human T-ALL through concomitant regulation of tumor metabolism and leukemic cell migration.