Janus kinase 2: a critical target in chronic myelogenous leukemia

Cancer Res. 2006 Jul 1;66(13):6468-72. doi: 10.1158/0008-5472.CAN-06-0025.

Abstract

The Bcr-Abl tyrosine kinase is the causative factor in most chronic myelogenous leukemia (CML) patients. We have shown that Bcr-Abl is associated with a cluster of signaling proteins, including Janus kinase (Jak) 2, growth factor receptor binding protein 2-associated binder (Gab) 2, Akt, and glycogen synthase kinase (GSK)-3beta. Treatment of CML cell lines and mouse Bcr-Abl+ 32D cells with either Jak2 short interfering RNA or Jak2 kinase inhibitor AG490 inhibited pTyr Gab2 and pSer Akt formation, inhibited the activation of nuclear factor-kappaB, and caused the activation of GSK-3beta, leading to the reduction of c-Myc. Importantly, BaF3 cells expressing T315I and E255K imatinib-resistant mutants of Bcr-Abl underwent apoptosis on exposure to AG490 yet were resistant to imatinib. Similar to wild-type Bcr-Abl+ cells, inhibition of Jak2 by Ag490 treatment resulted in decrease of pSer Akt and c-Myc in imatinib-resistant cells. These results identify Jak2 as a potentially important therapeutic target for CML.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Benzamides
  • Cell Line, Tumor
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Fusion Proteins, bcr-abl / biosynthesis
  • Fusion Proteins, bcr-abl / metabolism*
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Imatinib Mesylate
  • Janus Kinase 2
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / enzymology*
  • Mice
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism
  • Phosphorylation
  • Piperazines / pharmacology
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Proto-Oncogene Proteins c-myc / biosynthesis
  • Pyrimidines / pharmacology
  • RNA, Small Interfering / genetics
  • Signal Transduction
  • Transfection
  • Tyrphostins / pharmacology

Substances

  • Antineoplastic Agents
  • Benzamides
  • Enzyme Inhibitors
  • NF-kappa B
  • Piperazines
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-myc
  • Pyrimidines
  • RNA, Small Interfering
  • Tyrphostins
  • alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
  • Imatinib Mesylate
  • Protein-Tyrosine Kinases
  • Fusion Proteins, bcr-abl
  • JAK2 protein, human
  • Jak2 protein, mouse
  • Janus Kinase 2
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3