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 language | English |
|---|---|
| Pages (from-to) | 2812-2821 |
| Number of pages | 10 |
| Journal | Blood |
| Volume | 116 |
| Issue number | 15 |
| DOIs | |
| State | Published - Oct 14 2010 |
| Externally published | Yes |
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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 journal › Article
}
TY - JOUR
T1 - Depletion of L3MBTL1 promotes the erythroid differentiation of human hematopoietic progenitor cells
T2 - Possible role in 20q - Polycythemia vera
AU - Perna, Fabiana
AU - Gurvich, Nadia
AU - Hoya-Arias, Ruben
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
PY - 2010/10/14
Y1 - 2010/10/14
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=77957945719&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77957945719&partnerID=8YFLogxK
U2 - 10.1182/blood-2010-02-270611
DO - 10.1182/blood-2010-02-270611
M3 - Article
C2 - 20585043
AN - SCOPUS:77957945719
VL - 116
SP - 2812
EP - 2821
JO - Blood
JF - Blood
SN - 0006-4971
IS - 15
ER -