The preferentially expressed antigen in melanoma (PRAME) inhibits myeloid differentiation in normal hematopoietic and leukemic progenitor cells.
The preferentially expressed antigen in melanoma (PRAME) is expressed in several hematologic malignancies, but either is not expressed or is expressed at only low levels in normal hematopoietic cells, making it a target for cancer therapy. PRAME is a tumor-associated antigen and has been described as a corepressor of retinoic acid signaling in solid tumor cells, but its function in hematopoietic cells is unknown. PRAME mRNA expression increased with chronic myeloid leukemia (CML) disease progression and its detection in late chronic-phase CML patients before tyrosine kinase inhibitor therapy was associated with poorer therapeutic responses and ABL tyrosine kinase domain point mutations. In leukemia cell lines, PRAME protein expression inhibited granulocytic differentiation only in cell lines that differentiate along this lineage after all-trans retinoic acid (ATRA) exposure. Forced PRAME expression in normal hematopoietic progenitors, however, inhibited myeloid differentiation both in the presence and absence of ATRA, and this phenotype was reversed when PRAME was silenced in primary CML progenitors. These observations suggest that PRAME inhibits myeloid differentiation in certain myeloid leukemias, and that its function in these cells is lineage and phenotype dependent. Lastly, these observations suggest that PRAME is a target for both prognostic and therapeutic applications.
Oehler
Vivian G
VG
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. voehler@u.washington.edu
Guthrie
Katherine A
KA
Cummings
Carrie L
CL
Sabo
Kathleen
K
Wood
Brent L
BL
Gooley
Ted
T
Yang
Taimei
T
Epping
Mirjam T
MT
Shou
Yaping
Y
Pogosova-Agadjanyan
Era
E
Ladne
Paula
P
Stirewalt
Derek L
DL
Abkowitz
Janis L
JL
Radich
Jerald P
JP
D000951:Antigens, Neoplasm / Q000096:biosynthesis*; D000970:Antineoplastic Agents / Q000494:pharmacology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D020868:Gene Silencing; D006098:Granulocytes / Q000378:metabolism* / Q000473:pathology; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; C404944:PRAME protein, human; D047428:Protein Kinase Inhibitors; D014212:Tretinoin; D016315:Proto-Oncogene Proteins c-abl