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

J Clin Invest. 2021 Aug 16;131(16):e143119. doi: 10.1172/JCI143119.


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.

Keywords: Cancer; Cell Biology; Cell cycle; Cell migration/adhesion; Oncology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • Biomarkers, Tumor
  • CXCR4 protein, human
  • IPO9 protein, human
  • Karyopherins
  • MYC protein, human
  • Proto-Oncogene Proteins c-myc
  • Receptors, CXCR4
  • Phosphofructokinase-1, Type C
  • PFKP protein, human
  • CDK6 protein, human
  • Cyclin-Dependent Kinase 6