Depletion of L3MBTL1 promotes the erythroid differentiation of human hematopoietic progenitor cells: Possible role in 20q - Polycythemia vera Journal Article

Authors: Perna, F.; Gurvich, N.; Hoya-Arias, R. ; Abdel-Wahab, O.; Levine, R. L.; Asai, T.; Voza, F.; Menendez, S.; Wang, L.; Liu, F.; Zhao, X.; Nimer, S. D.
Article Title: Depletion of L3MBTL1 promotes the erythroid differentiation of human hematopoietic progenitor cells: Possible role in 20q - Polycythemia vera
Abstract: L3MBTL1, the human homolog of the Drosophila L(3)MBT polycomb group tumor suppressor gene, is located on chromosome 20q12, within the common deleted region identified in patients with 20q deletion-associated polycythemia vera, myelodysplastic syndrome, and acute myeloid leukemia. L3MBTL1 is expressed within hematopoietic CD34+ cells; thus, it may contribute to the pathogenesis of these disorders. To define its role in hematopoiesis, we knocked down L3MBTL1 expression in primary hematopoietic stem/progenitor (ie, CD34 +) cells isolated from human cord blood (using short hairpin RNAs) and observed an enhanced commitment to and acceleration of erythroid differentiation. Consistent with this effect, overexpression of L3MBTL1 in primary hematopoietic CD34+ cells as well as in 20q- cell lines restricted erythroid differentiation. Furthermore, L3MBTL1 levels decrease during hemin-induced erythroid differentiation or erythropoietin exposure, suggesting a specific role for L3MBTL1 down-regulation in enforcing cell fate decisions toward the erythroid lineage. Indeed, L3MBTL1 knockdown enhanced the sensitivity of hematopoietic stem/progenitor cells to erythropoietin (Epo), with increased Epo-induced phosphorylation of STAT5, AKT, and MAPK as well as detectable phosphorylation in the absence of Epo. Our data suggest that haploinsufficiency of L3MBTL1 contributes to some (20q-) myeloproliferative neoplasms, especially polycythemia vera, by promoting erythroid differentiation. © 2010 by The American Society of Hematology.
Keywords: signal transduction; mitogen activated protein kinase; protein kinase b; controlled study; gene; cd34 antigen; gene expression; erythropoietin; erythropoiesis; map kinase signaling system; neoplasm proteins; rna, small interfering; cell differentiation; cell lineage; enzyme phosphorylation; proto-oncogene proteins c-akt; hematopoietic stem cells; umbilical cord blood; base sequence; gene control; hematopoiesis; hematopoietic stem cell; stat5 protein; stat5 transcription factor; antigens, cd34; gene knockdown techniques; polycythemia vera; chromosome 20q; k562 cells; chromosomes, human, pair 20; hemin; l3mbtl1 gene
Journal Title: Blood
Volume: 116
Issue: 15
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2010-10-14
Start Page: 2812
End Page: 2821
Language: English
DOI: 10.1182/blood-2010-02-270611
PUBMED: 20585043
PROVIDER: scopus
PMCID: PMC2974589
Notes: --- - "Cited By (since 1996): 1" - "Export Date: 20 April 2011" - "CODEN: BLOOA" - "Source: Scopus"
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MSK Authors
  1. Stephen D Nimer
    339 Nimer
  2. Ross Levine
    469 Levine
  3. Takashi Asai
    12 Asai
  4. Xinyang Zhao
    29 Zhao
  5. Fabiana Perna
    45 Perna
  6. Lan Wang
    14 Wang
  7. Fan Rong Liu
    16 Liu
  8. Francesca Alexandra Voza
    18 Voza