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

Fabiana Perna, Nadia Gurvich, Ruben Hoya-Arias, Omar Abdel-Wahab, Ross L. Levine, Takashi Asai, Francesca Voza, Silvia Menendez, Lan Wang, Fan Liu, Xinyang Zhao, Stephen D Nimer

Research output: Contribution to journalArticle

35 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2812-2821
Number of pages10
JournalBlood
Volume116
Issue number15
DOIs
StatePublished - Oct 14 2010
Externally publishedYes

Fingerprint

Polycythemia Vera
Erythropoietin
Hematopoietic Stem Cells
Phosphorylation
Haploinsufficiency
Hemin
Myelodysplastic Syndromes
Hematopoiesis
Chromosomes
Stem cells
Tumor Suppressor Genes
Fetal Blood
Acute Myeloid Leukemia
Small Interfering RNA
Drosophila
Tumors
Blood
Down-Regulation
Genes
Cells

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Depletion of L3MBTL1 promotes the erythroid differentiation of human hematopoietic progenitor cells : Possible role in 20q - Polycythemia vera. / Perna, Fabiana; Gurvich, Nadia; Hoya-Arias, Ruben; Abdel-Wahab, Omar; Levine, Ross L.; Asai, Takashi; Voza, Francesca; Menendez, Silvia; Wang, Lan; Liu, Fan; Zhao, Xinyang; Nimer, Stephen D.

In: Blood, Vol. 116, No. 15, 14.10.2010, p. 2812-2821.

Research output: Contribution to journalArticle

Perna, F, Gurvich, N, Hoya-Arias, R, Abdel-Wahab, O, Levine, RL, Asai, T, Voza, F, Menendez, S, Wang, L, Liu, F, Zhao, X & Nimer, SD 2010, 'Depletion of L3MBTL1 promotes the erythroid differentiation of human hematopoietic progenitor cells: Possible role in 20q - Polycythemia vera', Blood, vol. 116, no. 15, pp. 2812-2821. https://doi.org/10.1182/blood-2010-02-270611
Perna, Fabiana ; Gurvich, Nadia ; Hoya-Arias, Ruben ; Abdel-Wahab, Omar ; Levine, Ross L. ; Asai, Takashi ; Voza, Francesca ; Menendez, Silvia ; Wang, Lan ; Liu, Fan ; Zhao, Xinyang ; Nimer, Stephen D. / Depletion of L3MBTL1 promotes the erythroid differentiation of human hematopoietic progenitor cells : Possible role in 20q - Polycythemia vera. In: Blood. 2010 ; Vol. 116, No. 15. pp. 2812-2821.
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AU - Abdel-Wahab, Omar

AU - Levine, Ross L.

AU - Asai, Takashi

AU - Voza, Francesca

AU - Menendez, Silvia

AU - Wang, Lan

AU - Liu, Fan

AU - Zhao, Xinyang

AU - Nimer, Stephen D

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