Depletion of L3MBTL1 promotes the erythroid differentiation of human hematopoietic progenitor cells: possible role in 20q- polycythemia vera.
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.
Perna
Fabiana
F
Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, NY, USA.
Gurvich
Nadia
N
Hoya-Arias
Ruben
R
Abdel-Wahab
Omar
O
Levine
Ross L
RL
Asai
Takashi
T
Voza
Francesca
F
Menendez
Silvia
S
Wang
Lan
L
Liu
Fan
F
Zhao
Xinyang
X
Nimer
Stephen D
SD
D018952:Antigens, CD34 / Q000378:metabolism; D001483:Base Sequence; D002868:Chromosomal Proteins, Non-Histone; D002890:Chromosomes, Human, Pair 20 / Q000235:genetics*; D004920:Erythropoiesis / Q000235:genetics / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006412:Hematopoietic Stem Cells / Q000473:pathology / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D020014:K562 Cells; D020935:MAP Kinase Signaling System; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D011087:Polycythemia Vera / Q000097:blood / Q000209:etiology* / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins
D018952:Antigens, CD34; D002868:Chromosomal Proteins, Non-Histone; C120887:L3MBTL1 protein, human; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D050799:STAT5 Transcription Factor; D025521:Tumor Suppressor Proteins; D051057:Proto-Oncogene Proteins c-akt