Loss of Forkhead box M1 promotes erythropoiesis through increased proliferation of erythroid progenitors.
Forkhead box M1 (FOXM1) belongs to the forkhead/winged-helix family of transcription factors and regulates a network of proliferation-associated genes. Its abnormal upregulation has been shown to be a key driver of cancer progression and an initiating factor in oncogenesis. FOXM1 is also highly expressed in stem/progenitor cells and inhibits their differentiation, suggesting that FOXM1 plays a role in the maintenance of multipotency. However, the exact molecular mechanisms by which FOXM1 regulates human stem/progenitor cells are still uncharacterized. To understand the role of FOXM1 in normal hematopoiesis, human cord blood CD34+cells were transduced with FOXM1 short hairpin ribonucleic acid (shRNA) lentivirus. Knockdown of FOXM1 resulted in a 2-fold increase in erythroid cells compared to myeloid cells. Additionally, knockdown of FOXM1 increased bromodeoxyuridine (BrdU) incorporation in erythroid cells, suggesting greater proliferation of erythroid progenitors. We also observed that the defective phosphorylation of FOXM1 by checkpoint kinase 2 (CHK2) or cyclin-dependent kinases 1/2 (CDK1/2) increased the erythroid population in a manner similar to knockdown of FOXM1. Finally, we found that an inhibitor of FOXM1, forkhead domain inhibitor-6 (FDI-6), increased red blood cell numbers through increased proliferation of erythroid precursors. Overall, our data suggest a novel function of FOXM1 in normal human hematopoiesis.
Department of Pediatrics, Stanford University School of Medicine, CA, USA.
Minyoung
M
Youn
Department of Pediatrics, Stanford University School of Medicine, CA, USA.
Nan
N
Wang
Department of Pediatrics, Stanford University School of Medicine, CA, USA.
Corinne
C
LaVasseur
Department of Pediatrics, Stanford University School of Medicine, CA, USA.
Elena
E
Bibikova
Department of Pediatrics, Stanford University School of Medicine, CA, USA.
Sharon
S
Kam
Department of Pediatrics, Stanford University School of Medicine, CA, USA.
Bertil
B
Glader
Department of Pediatrics, Stanford University School of Medicine, CA, USA.
Kathleen M
KM
Sakamoto
Department of Pediatrics, Stanford University School of Medicine, CA, USA anunarla@stanford.edu.
Anupama
A
Narla
D018952:Antigens, CD34 / Q000097:blood; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D064447:Checkpoint Kinase 2 / Q000378:metabolism; D041905:Erythroid Cells / Q000378:metabolism; D015672:Erythroid Precursor Cells / Q000378:metabolism*; D004920:Erythropoiesis / Q000235:genetics*; D005312:Fetal Blood / Q000166:cytology / Q000378:metabolism; D000072278:Forkhead Box Protein M1 / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D006801:Humans; D020014:K562 Cells; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D034622:RNA Interference; D013876:Thiophenes / Q000494:pharmacology
D018952:Antigens, CD34; C000603299:FDI-6 compound; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D011725:Pyridines; D013876:Thiophenes; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human