Faculty Collaboration Database

Nuclear PFKP promotes CXCR4-dependent infiltration by T cell acute lymphoblastic leukemia. J Clin Invest 2021 Aug 16;131(16)

Date

07/14/2021

Pubmed ID

34255748

Pubmed Central ID

PMC8363288

DOI

10.1172/JCI143119

Scopus ID

2-s2.0-85113146308 (requires institutional sign-in at Scopus site)   21 Citations

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.

Author List

Gao X, Qin S, Wu Y, Chu C, Jiang B, Johnson RH, Kuang D, Zhang J, Wang X, Mehta A, Tew KD, Leone GW, Yu XZ, Wang H

Authors

Roger H. Johnson PhD Associate Professor in the Biophysics department at Medical College of Wisconsin
Gustavo Leone PhD Sr Associate Dean, Director, Professor in the Biochemistry department at Medical College of Wisconsin
Yongxia Wu PhD Assistant Professor in the Microbiology and Immunology department at Medical College of Wisconsin
Xue-Zhong Yu MD Professor in the Microbiology and Immunology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Active Transport, Cell Nucleus
Animals
Biomarkers, Tumor
Cyclin-Dependent Kinase 6
Female
Humans
Karyopherins
Lymphocytes, Tumor-Infiltrating
Male
Mice
Mice, Inbred NOD
Mice, SCID
Middle Aged
Models, Molecular
Neoplasm Invasiveness
Phosphofructokinase-1, Type C
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Prognosis
Protein Interaction Domains and Motifs
Proto-Oncogene Proteins c-myc
Receptors, CXCR4
Tumor Cells, Cultured