4.8 Article

RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia

期刊

JOURNAL OF CLINICAL INVESTIGATION
卷 131, 期 6, 页码 -

出版社

AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI141566

关键词

-

资金

  1. NIH National Cancer Institute (NCI) [R01 CA237165]
  2. NIH National Center for Advancing Translational Sciences (NCATS) Clinical and Translational Science Awards (CTSA) [8UL1TR000041]
  3. NIH NCI Cancer Center Support Grant [P30CA118100]
  4. University of New Mexico Autophagy, Inflammation & Metabolism Center (AIM) [P20GM121176, U24 CA114766, R35 CA197695]
  5. Research Foundation Flanders (FWO)
  6. Flemish Agency for Innovation by Science and Technology
  7. National Health and Medical Research Council of Australia [APP1142627, APP1059804, APP1157871]
  8. Kinderkankerfonds
  9. Stand up to Cancer (the Flemish Cancer Society)

向作者/读者索取更多资源

The study demonstrates that the upregulation of RUNX2 acts as a dependency factor in high-risk subtypes of human T-ALL by regulating tumor metabolism and leukemic cell migration simultaneously.
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.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.8
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据