OBJECTIVE: Clonal stem cell proliferation and increased erythrocyte mass are hallmarks of the myeloproliferative disorder polycythemia vera (PV). The molecular basis of PV is unknown. METHODS: We carried out a genome-wide screening for loss of heterozygosity (LOH) and analyzed candidate genes within the LOH loci. RESULTS: Three genomic regions were identified on chromosomes 9p, 10q, and 11q. The presence of these LOHs in both myeloid and lymphoid cells indicated their stem cell origin. The 9pLOH prevalence is approximately 33% and is the most frequent chromosomal lesion described in PV so far. We report that the 9pLOH is due to mitotic recombination and therefore remains undetectable by cytogenetic analysis. Nineteen candidate genes were selected within the 9pLOH region for sequencing and expression analysis. No mutations were found in these genes; however, unexpectedly, increased expression of the transcription factor NFI-B was detected in granulocytes and CD34(+) cells in PV with 9pLOH. Since a member of the NFI gene family (NFI-X) was reported to result in TGF-beta resistance when overexpressed in vitro (TGF-beta is a known inhibitor of hematopoiesis), we transfected the NFI-B gene to the mouse 32D cell line. We found that overexpression of the NFI-B gene confers TGF-beta resistance in vitro. CONCLUSIONS: We characterized a new region on chromosome 9p frequently involved in LOH in PV. Analysis of genes within this 9pLOH region revealed increased expression of the NFI-B gene. Our in vitro studies suggest that TGF-beta resistance may be the physiologic mechanism of clonal stem cell expansion in PV.
OBJECTIVE: Clonal stem cell proliferation and increased erythrocyte mass are hallmarks of the myeloproliferative disorder polycythemia vera (PV). The molecular basis of PV is unknown. METHODS: We carried out a genome-wide screening for loss of heterozygosity (LOH) and analyzed candidate genes within the LOH loci. RESULTS: Three genomic regions were identified on chromosomes 9p, 10q, and 11q. The presence of these LOHs in both myeloid and lymphoid cells indicated their stem cell origin. The 9pLOH prevalence is approximately 33% and is the most frequent chromosomal lesion described in PV so far. We report that the 9pLOH is due to mitotic recombination and therefore remains undetectable by cytogenetic analysis. Nineteen candidate genes were selected within the 9pLOH region for sequencing and expression analysis. No mutations were found in these genes; however, unexpectedly, increased expression of the transcription factor NFI-B was detected in granulocytes and CD34(+) cells in PV with 9pLOH. Since a member of the NFI gene family (NFI-X) was reported to result in TGF-beta resistance when overexpressed in vitro (TGF-beta is a known inhibitor of hematopoiesis), we transfected the NFI-B gene to the mouse 32D cell line. We found that overexpression of the NFI-B gene confers TGF-beta resistance in vitro. CONCLUSIONS: We characterized a new region on chromosome 9p frequently involved in LOH in PV. Analysis of genes within this 9pLOH region revealed increased expression of the NFI-B gene. Our in vitro studies suggest that TGF-beta resistance may be the physiologic mechanism of clonal stem cell expansion in PV.
Authors: Sabina I Swierczek; Donghoon Yoon; Christine Bellanné-Chantelot; Soo Jin Kim; Cécile Saint-Martin; Francois Delhommeau; Albert Najman; Josef T Prchal Journal: Haematologica Date: 2011-01-27 Impact factor: 9.941
Authors: Andrew J Dunbar; Lukasz P Gondek; Christine L O'Keefe; Hideki Makishima; Manjot S Rataul; Hadrian Szpurka; Mikkael A Sekeres; Xiao Fei Wang; Michael A McDevitt; Jaroslaw P Maciejewski Journal: Cancer Res Date: 2008-12-15 Impact factor: 12.701