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Physiological Jak2V617F expression causes a lethal myeloproliferative neoplasm with differential effects on hematopoietic stem and progenitor cells.

We report a Jak2V617F knockin mouse myeloproliferative neoplasm (MPN) model resembling human polycythemia vera (PV). The MPN is serially transplantable and we demonstrate that the hematopoietic stem cell (HSC) compartment has the unique capacity for disease initiation but does not have a significant selective competitive advantage over wild-type HSCs. In contrast, myeloid progenitor populations are expanded and skewed toward the erythroid lineage, but cannot transplant the disease. Treatment with a JAK2 kinase inhibitor ameliorated the MPN phenotype, but did not eliminate the disease-initiating population. These findings provide insights into the consequences of JAK2 activation on HSC differentiation and function and have the potential to inform therapeutic approaches to JAK2V617F-positive MPN.

Pubmed ID: 20541703

Authors

  • Mullally A
  • Lane SW
  • Ball B
  • Megerdichian C
  • Okabe R
  • Al-Shahrour F
  • Paktinat M
  • Haydu JE
  • Housman E
  • Lord AM
  • Wernig G
  • Kharas MG
  • Mercher T
  • Kutok JL
  • Gilliland DG
  • Ebert BL

Journal

Cancer cell

Publication Data

June 15, 2010

Associated Grants

  • Agency: NCI NIH HHS, Id: P01 CA 66996-11
  • Agency: NCI NIH HHS, Id: P01 CA066996
  • Agency: NIDDK NIH HHS, Id: P30 DK49216
  • Agency: NHLBI NIH HHS, Id: R01 HL082945
  • Agency: NHLBI NIH HHS, Id: R01 HL082945-04
  • Agency: NHLBI NIH HHS, Id: R01 HL082950
  • Agency: NHLBI NIH HHS, Id: T32HL0763

Mesh Terms

  • Amino Acid Substitution
  • Animals
  • Antigens, CD
  • Bone Marrow
  • Bone Marrow Cells
  • Bone Marrow Transplantation
  • Cell Count
  • Cell Differentiation
  • Disease Models, Animal
  • Erythroid Precursor Cells
  • Erythropoietin
  • Gene Expression
  • Gene Expression Profiling
  • Hematocrit
  • Hematopoietic Stem Cell Transplantation
  • Hematopoietic Stem Cells
  • Heterozygote
  • Humans
  • Janus Kinase 2
  • Megakaryocyte Progenitor Cells
  • Megakaryocyte-Erythroid Progenitor Cells
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Myeloid Progenitor Cells
  • Myeloproliferative Disorders
  • Polycythemia Vera
  • Protein Kinase Inhibitors
  • Pyrrolidines
  • Spleen
  • Sulfonamides
  • Survival Analysis