2. Academic Validation
  3. PHF6 and JAK3 mutations cooperate to drive T-cell acute lymphoblastic leukemia progression

PHF6 and JAK3 mutations cooperate to drive T-cell acute lymphoblastic leukemia progression

  • Leukemia. 2022 Feb;36(2):370-382. doi: 10.1038/s41375-021-01392-1.
Shengnan Yuan  # 1,  Xiaomin Wang  # 2 3,  Shuaibing Hou 1,  Tengxiao Guo 1,  Yanjie Lan 1,  Shuang Yang 1,  Fei Zhao 1,  Juan Gao 1,  Yuxia Wang 1,  Yajing Chu 1,  Jun Shi 1,  Tao Cheng 1,  Weiping Yuan 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
  • 2 State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China. wangxiaomin@ihcams.ac.cn.
  • 3 Department of Neuro-oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. wangxiaomin@ihcams.ac.cn.
  • 4 State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China. wpyuan@ihcams.ac.cn.
  • # Contributed equally.
PMID: 34465864 DOI: 10.1038/s41375-021-01392-1
Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is a malignant hematologic disease caused by gene mutations in T-cell progenitors. As an important epigenetic regulator, PHF6 mutations frequently coexist with JAK3 mutations in T-ALL patients. However, the role(s) of PHF6 mutations in JAK3-driven leukemia remain unclear. Here, the cooperation between JAK3 activation and PHF6 inactivation is examined in leukemia patients and in mice models. We found that the average survival time is shorter in patients with JAK/STAT and PHF6 comutation than that in other patients, suggesting a potential role of PHF6 in leukemia progression. We subsequently found that Phf6 deficiency promotes JAK3M511I-induced T-ALL progression in mice by inhibiting the Bai1-Mdm2-P53 signaling pathway, which is independent of the JAK3/STAT5 signaling pathway. Furthermore, combination therapy with a JAK3 Inhibitor (tofacitinib) and a MDM2 Inhibitor (idasanutlin) reduces the Phf6 KO and JAK3M511I leukemia burden in vivo. Taken together, our study suggests that combined treatment with JAK3 and MDM2 inhibitors may potentially increase the drug benefit for T-ALL patients with PHF6 and JAK3 comutation.

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