Pak1 gene functioned differentially in different BCR-ABL subtypes in leukemiagenesis and treatment response through STAT5 pathway

Leuk Res. 2019 Apr:79:6-16. doi: 10.1016/j.leukres.2019.01.012. Epub 2019 Jan 24.

Abstract

The BCR-ABL fusion gene (BCR-ABL) has different subtypes such as p210 and p190 with p190 appear to lead to a worse prognosis. To explore the mechanism of difference in pathogenesis and prognosis in different BCR-ABL subtype-related leukemia, expression profile microarray analysis was conducted between p190 and p210 patients and verified by RT-PCR. The p21-activated kinase (PAK1) gene was chosen and regulation of the PAK1-STAT5 biological axis and its influence on proliferation and apoptosis in leukemia cells were also analyzed. The results showed that PAK1 might be an important molecular mechanism of the pathogenic difference between different BCR-ABL subtypes. In P210 (+) chronic myelogenous leukemia (CML), down-regulated PAK1 gene expressions may lead to the suppression of cell proliferation and promotion of apoptosis through phosphorylation of STAT5, with a reverse effect in P190 (+) acute lymphoblastic leukemia(ALL), especially acute B lymphoblastic leukemia (B-ALL). Additionally, in P210 (+) CML, down-regulated PAK1 expression may enhance the effect of TKI, whereas the reverse is true in P190 (+) B-ALL, demonstrating that PAK1 might also be an important therapeutic target between different BCR-ABL subtypes.

Keywords: Acute lymphocytic leukemia (ALL); BCR-ABL subtype; Chronic myelogenous leukeamia (CML); PAK1 gene.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Transformation, Neoplastic / genetics*
  • Fusion Proteins, bcr-abl / classification
  • Fusion Proteins, bcr-abl / genetics*
  • Gene Expression Profiling
  • Gene Expression Regulation, Leukemic
  • HEK293 Cells
  • Humans
  • K562 Cells
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / therapy
  • Microarray Analysis
  • Mutation
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma* / genetics
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma* / metabolism
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma* / pathology
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma* / therapy
  • STAT5 Transcription Factor / physiology*
  • Signal Transduction / genetics
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins / physiology*
  • p21-Activated Kinases / genetics
  • p21-Activated Kinases / physiology*

Substances

  • STAT5 Transcription Factor
  • STAT5A protein, human
  • Tumor Suppressor Proteins
  • Fusion Proteins, bcr-abl
  • PAK1 protein, human
  • p21-Activated Kinases