Characterization of chronic myeloid leukemia stem cells.
Although tyrosine kinase inhibitors have redefined the care of chronic myeloid leukemia (CML), these agents have not proved curative, likely due to resistance of the leukemia stem cells (LSC). While a number of potential therapeutic targets have emerged in CML, their expression in the LSC remains largely unknown. We therefore isolated subsets of CD34(+) stem/progenitor cells from normal donors and from patients with chronic phase or blast crisis CML. These cell subsets were then characterized based on ability to engraft immunodeficient mice and expression of candidate therapeutic targets. The CD34(+)CD38(-) CML cell population with high aldehyde dehydrogenase (ALDH) activity was the most enriched for immunodeficient mouse engrafting capacity. The putative targets: PROTEINASE 3, SURVIVIN, and hTERT were expressed only at relatively low levels by the CD34(+)CD38(-)ALDH(high) CML cells, similar to the normal CD34(+)CD38(-)ALDH(high) cells and less than in the total CML CD34(+) cells. In fact, the highest expression of these antigens was in normal, unfractionated CD34(+) cells. In contrast, PRAME and WT1 were more highly expressed by all CML CD34(+) subsets than their normal counterparts. Thus, ALDH activity appears to enrich for CML stem cells, which display an expression profile that is distinct from normal stem/progenitor cells and even the CML progenitors. Indeed, expression of a putative target by the total CD34(+) population in CML does not guarantee expression by the LSC. These expression patterns suggest that PROTEINASE 3, SURVIVIN, and hTERT are not optimal therapeutic targets in CML stem cells; whereas PRAME and WT1 seem promising.
Division of Hematology, Department of Medicine, The Johns Hopkins University School of Medicine and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA. jgerber2@jhmi.edu
Jonathan M
JM
Gerber
Lu
L
Qin
Jeanne
J
Kowalski
B Douglas
BD
Smith
Constance A
CA
Griffin
Milada S
MS
Vala
Michael I
MI
Collector
Brandy
B
Perkins
Marianna
M
Zahurak
William
W
Matsui
Christopher D
CD
Gocke
Saul J
SJ
Sharkis
Hyam I
HI
Levitsky
Richard J
RJ
Jones
D051997:ADP-ribosyl Cyclase 1 / Q000096:biosynthesis; D000328:Adult; D000368:Aged; D000444:Aldehyde Dehydrogenase / Q000096:biosynthesis; D000818:Animals; D018952:Antigens, CD34 / Q000096:biosynthesis; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis / Q000235:genetics; D008875:Middle Aged; D053146:Myeloblastin / Q000096:biosynthesis / Q000235:genetics; D009368:Neoplasm Transplantation; D012333:RNA, Messenger / Q000096:biosynthesis; D000077022:Survivin; D019098:Telomerase / Q000096:biosynthesis / Q000235:genetics; D025721:WT1 Proteins / Q000096:biosynthesis / Q000235:genetics
D018952:Antigens, CD34; D000951:Antigens, Neoplasm; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; C404944:PRAME protein, human; D012333:RNA, Messenger; D000077022:Survivin; D025721:WT1 Proteins; D000444:Aldehyde Dehydrogenase; C509186:TERT protein, human; D019098:Telomerase; D051997:ADP-ribosyl Cyclase 1; D053146:Myeloblastin