The interleukin-3 receptor alpha chain is a unique marker for human acute myelogenous leukemia stem cells.
Recent studies suggest that the population of malignant cells found in human acute myelogenous leukemia (AML) arises from a rare population of leukemic stem cells (LSCs). LSCs have been documented for nearly all AML subtypes and have been phenotypically described as CD34+/CD38- or CD34+/HLA-DR-. Given the potentially critical role of these primitive cells in perpetuating leukemic disease, we sought to further investigate their molecular and cellular characteristics. Flow cytometric studies using primary AML tissue showed that the interleukin-3 receptor alpha chain (IL-3Ralpha or CD123) was strongly expressed in CD34+/CD38- cells (98 +/- 2% positive) from 16 of 18 primary specimens. Conversely, normal bone marrow derived CD34+/CD38- cells showed virtually no detectable expression of the CD123 antigen. To assess the functional role of IL-3Ralpha positive cells, purified CD34+/CD123+ leukemia cells were transplanted into immune deficient NOD/SCID mice. These experiments showed that CD123+ cells were competent to establish and maintain leukemic populations in vivo. To begin to elucidate a biological role for CD123 in leukemia, primary AML samples were analyzed with respect to signal transduction activity in the MAPK, Akt, and Stat5 pathways. Phosphorylation was not detected in response to IL-3 stimulation, thereby suggesting CD123 is not active in conventional IL-3-mediated signaling. Collectively, these data indicate that CD123 represents a unique marker for primitive leukemic stem cells. Given the strong expression of this receptor on LSCs, we propose that targeting of CD123 may be a promising strategy for the preferential ablation of AML cells.
Jordan
C T
CT
Division of Hematology/Oncology, University of Kentucky Medical Center, Lexington 40536-0093, USA.
Upchurch
D
D
Szilvassy
S J
SJ
Guzman
M L
ML
Howard
D S
DS
Pettigrew
A L
AL
Meyerrose
T
T
Rossi
R
R
Grimes
B
B
Rizzieri
D A
DA
Luger
S M
SM
Phillips
G L
GL
D000818:Animals; D006801:Humans; D016130:Immunophenotyping; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D016185:Receptors, Interleukin-3 / Q000737:chemistry / Q000378:metabolism*; D013234:Stem Cells / Q000276:immunology / Q000378:metabolism*
D016185:Receptors, Interleukin-3