Nuclear PFKP promotes CXCR4-dependent infiltration by T cell acute lymphoblastic leukemia
Xueliang Gao, … , Xue-Zhong Yu, Haizhen Wang
Xueliang Gao, … , Xue-Zhong Yu, Haizhen Wang
Published July 13, 2021
Citation Information: J Clin Invest. 2021;131(16):e143119. https://doi.org/10.1172/JCI143119.
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Research Article Cell biology Oncology Article has an altmetric score of 12

Nuclear PFKP promotes CXCR4-dependent infiltration by T cell acute lymphoblastic leukemia

Abstract

PFKP (phosphofructokinase, platelet), the major isoform of PFK1 expressed in T cell acute lymphoblastic leukemia (T-ALL), is predominantly expressed in the cytoplasm to carry out its glycolytic function. Our study showed that PFKP is a nucleocytoplasmic shuttling protein with functional nuclear export and nuclear localization sequences (NLSs). Cyclin D3/CDK6 facilitated PFKP nuclear translocation by dimerization and by exposing the NLS of PFKP to induce the interaction between PFKP and importin 9. Nuclear PFKP stimulated the expression of C-X-C chemokine receptor type 4 (CXCR4), a chemokine receptor regulating leukemia homing/infiltration, to promote T-ALL cell invasion, which depended on the activity of c-Myc. In vivo experiments showed that nuclear PFKP promoted leukemia homing/infiltration into the bone marrow, spleen, and liver, which could be blocked with CXCR4 antagonists. Immunohistochemical staining of tissues from a clinically well-annotated cohort of T cell lymphoma/leukemia patients showed nuclear PFKP localization in invasive cancers, but not in nonmalignant T lymph node or reactive hyperplasia. The presence of nuclear PFKP in these specimens correlated with poor survival in patients with T cell malignancy, suggesting the potential utility of nuclear PFKP as a diagnostic marker.

Authors

Xueliang Gao, Shenghui Qin, Yongxia Wu, Chen Chu, Baishan Jiang, Roger H. Johnson, Dong Kuang, Jie Zhang, Xi Wang, Anand Mehta, Kenneth D. Tew, Gustavo W. Leone, Xue-Zhong Yu, Haizhen Wang

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Figure 8

Nuclear PFKP is associated with the aggressiveness of T cell lymphoma/leukemia.

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Nuclear PFKP is associated with the aggressiveness of T cell lymphoma/le...
(A) Immunohistochemistry (IHC) shows nuclear localization of PFKP in aggressive T cell lymphoma/leukemia. High-magnification image represents area indicated by the small rectangle. RH, reactive hyperplasia; PTCL, NOS, peripheral T cell lymphoma, not otherwise specified; AITL, angioimmunoblastic T cell lymphoma; NK/T, extranodal NK/T cell lymphoma, nasal type; T-LBL/ALL, T lymphoblastic lymphoma/acute lymphoblastic leukemia. Scale bar: 100 μm. (B) Percentage of positive nuclear PFKP staining in individual specimens. In total, 36 cases of normal, 16 cases of RH, 42 cases of AITL, 16 cases of PTCL, NOS, 33 cases of NK/T, and 10 cases of T-LBL/ALL were analyzed. (C) Positive nuclear PFKP staining is associated with poor survival in NK/T and AITL patients. Kaplan-Meier plot of overall survival of patients with negative or positive nuclear PFKP staining in NK/T and AITL groups. Red and blue lines represent patients positive and negative for nuclear PFKP staining, respectively. (D) Schematic showing that PFKP is a nucleocytoplasmic shuttling protein with functional nuclear export signal (NES) and nuclear localization signal (NLS) sequences. Cyclin D3/CDK6 facilitates PFKP nuclear translocation by exposing the NLS of PFKP, promoting the interaction between PFKP and importin-9. Nuclear PFKP stimulates the expression of CXCR4 to promote T-ALL cell invasiveness, which depends on the transcription factor c-Myc. Created with BioRender.com. *P < 0.05, ***P < 0.001, ****P < 0.0001 by 1-way ANOVA (B).