Identification of a myeloid committed progenitor as the cancer-initiating cell in acute promyelocytic leukemia.
Acute promyelocytic leukemia (APL) is characterized by a block in differentiation and accumulation of promyelocytes in the bone marrow and blood. The majority of APL patients harbor the t(15:17) translocation leading to expression of the fusion protein promyelocytic-retinoic acid receptor alpha. Treatment with retinoic acid leads to degradation of promyelocytic-retinoic acid receptor alpha protein and disappearance of leukemic cells; however, 30% of APL patients relapse after treatment. One potential mechanism for relapse is the persistence of cancer "stem" cells in hematopoietic organs after treatment. Using a novel sorting strategy we developed to isolate murine myeloid cells at distinct stages of differentiation, we identified a population of committed myeloid cells (CD34(+), c-kit(+), FcgammaRIII/II(+), Gr1(int)) that accumulates in the spleen and bone marrow in a murine model of APL. We observed that these cells are capable of efficiently generating leukemia in recipient mice, demonstrating that this population represents the APL cancer-initiating cell. These cells down-regulate the transcription factor CCAAT/enhancer binding protein alpha (C/EBPalpha) possibly through a methylation-dependent mechanism, indicating that C/EBPalpha deregulation contributes to transformation of APL cancer-initiating cells. Our findings provide further understanding of the biology of APL by demonstrating that a committed transformed progenitor can initiate and propagate the disease.
Center for Life Sciences, Harvard Medical School, Boston, MA, USA.
Florence C
FC
Guibal
Meritxell
M
Alberich-Jorda
Hideyo
H
Hirai
Alexander
A
Ebralidze
Elena
E
Levantini
Annalisa
A
Di Ruscio
Pu
P
Zhang
Barbara A
BA
Santana-Lemos
Donna
D
Neuberg
Amy J
AJ
Wagers
Eduardo M
EM
Rego
Daniel G
DG
Tenen
D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology*; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics; D040501:Calgranulin A / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D019175:DNA Methylation; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D053208:Kaplan-Meier Estimate; D015473:Leukemia, Promyelocytic, Acute / Q000097:blood / Q000235:genetics / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D020298:U937 Cells
D018952:Antigens, CD34; D022763:CCAAT-Enhancer-Binding Protein-alpha; D040501:Calgranulin A; D015514:Oncogene Proteins, Fusion; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D019009:Proto-Oncogene Proteins c-kit