Preferential nuclear accumulation of JAK2V617F in CD34+ but not in granulocytic, megakaryocytic, or erythroid cells of patients with Philadelphia-negative myeloproliferative neoplasia

Blood. 2010 Dec 23;116(26):6023-6. doi: 10.1182/blood-2010-08-302265. Epub 2010 Sep 22.

Abstract

Recently, Dawson et al identified a previously unrecognized nuclear role of JAK2 in the phosphorylation of histone H3 in hematopoietic cell lines. We searched nuclear JAK2 in total bone marrow (BM) cells and in 4 sorted BM cell populations (CD34(+), CD15(+), CD41(+), and CD71(+)) of 10 myeloproliferative neoplasia (MPN) patients with JAK2V617F mutation and 5 patients with wild-type JAK2 MPN. Confocal immunofluorescent images and Western blot analyses of nuclear and cytoplasmic fractions found nuclear JAK2 in CD34(+) cells of 10 of 10 JAK2-mutated patients but not in patients with wild-type JAK2. JAK2 was predominantly in the cytoplasmic fraction of differentiated granulocytic, megakaryocytic, or erythroid cells obtained from all patients. JAK2V617F up-regulates LMO2 in K562 and in JAK2V617F-positive CD34(+) cells. The selective JAK2 inhibitor AG490 normalizes the LMO2 levels in V617F-positive K562 and restores the cyto-plasmic localization of JAK2.

MeSH terms

  • Antigens, CD34 / metabolism*
  • Apoptosis
  • Blotting, Western
  • Bone Marrow / metabolism
  • Cell Nucleus / metabolism*
  • Cells, Cultured
  • Cytoplasm / metabolism
  • Erythroid Cells / metabolism*
  • Granulocytes / cytology
  • Granulocytes / metabolism*
  • Humans
  • Janus Kinase 2 / genetics*
  • Janus Kinase 2 / metabolism
  • K562 Cells
  • Megakaryocytes / cytology
  • Megakaryocytes / metabolism*
  • Microscopy, Fluorescence
  • Mutation / genetics
  • Myeloproliferative Disorders / genetics
  • Myeloproliferative Disorders / metabolism*
  • Myeloproliferative Disorders / pathology
  • Philadelphia Chromosome*
  • Phosphorylation
  • Prognosis
  • RNA, Messenger / genetics
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • Antigens, CD34
  • RNA, Messenger
  • JAK2 protein, human
  • Janus Kinase 2