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PMID: 16603627 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

The JAK2 V617F mutation occurs in hematopoietic stem cells in polycythemia vera and predisposes toward erythroid differentiation.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 103 ·No. 16 ·2006-04-18 ·Pages 6224-9

Jamieson CH, Gotlib J, Durocher JA, Chao MP, Mariappan MR, Lay M, Jones C, Zehnder JL, Lilleberg SL, Weissman IL

Abstract

Although a large proportion of patients with polycythemia vera (PV) harbor a valine-to-phenylalanine mutation at amino acid 617 (V617F) in the JAK2 signaling molecule, the stage of hematopoiesis at which the mutation arises is unknown. Here we isolated and characterized hematopoietic stem cells (HSC) and myeloid progenitors from 16 PV patient samples and 14 normal individuals, testing whether the JAK2 mutation could be found at the level of stem or progenitor cells and whether the JAK2 V617F-positive cells had altered differentiation potential. In all PV samples analyzed, there were increased numbers of cells with a HSC phenotype (CD34+CD38-CD90+Lin-) compared with normal samples. Hematopoietic progenitor assays demonstrated that the differentiation potential of PV was already skewed toward the erythroid lineage at the HSC level. The JAK2 V617F mutation was detectable within HSC and their progeny in PV. Moreover, the aberrant erythroid potential of PV HSC was potently inhibited with a JAK2 inhibitor, AG490.

MeSH Terms
ADP-ribosyl Cyclase 1/analysis Amino Acid Substitution/genetics Antigens, CD34/analysis Erythroid Precursor Cells/cytology,enzymology Hematopoiesis/genetics Hematopoietic Stem Cells/chemistry,cytology,enzymology Humans Janus Kinase 2 Phenylalanine/chemistry,genetics Point Mutation Polycythemia Vera/enzymology,genetics Protein Kinase Inhibitors/pharmacology Protein-Tyrosine Kinases/antagonists & inhibitors,genetics Proto-Oncogene Proteins/antagonists & inhibitors,genetics Thy-1 Antigens/analysis Tyrphostins/pharmacology Valine/chemistry,genetics
Chemicals
Antigens, CD34 Protein Kinase Inhibitors Proto-Oncogene Proteins Thy-1 Antigens Tyrphostins alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide Phenylalanine Protein-Tyrosine Kinases JAK2 protein, human Janus Kinase 2 ADP-ribosyl Cyclase 1 Valine
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Jamieson Catriona H M
Department of Medicine and Moores Cancer Center, University of California at San Diego, La Jolla, CA 92093, USA.
Gotlib Jason
Durocher Jeffrey A
Chao Mark P
Mariappan M Rajan
Lay Marla
Jones Carol
Zehnder James L
Lilleberg Stan L
Weissman Irving L
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0601462103
Published
2006-04-18
Epub
2006-00-07
Pages
6224-9
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC1434515
Subset
IM
Grants
NCI NIH HHS · 2P01CA49605 · United States
NCI NIH HHS · R01 CA086017 · United States
NCI NIH HHS · CA86017 · United States
NHLBI NIH HHS · K23 HL004409 · United States
NHLBI NIH HHS · K23 HL04409 · United States
NCI NIH HHS · P01 CA049605 · United States
NCI NIH HHS · R01 CA086065 · United States
NCI NIH HHS · CA086065 · United States
External Links
PubMed source DOI: 10.1073/pnas.0601462103 PMC Full Text View journal details
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