Abstract |
Childhood acute myeloid leukemia (AML) is a hematological malignancy in which tumor burden is continuously replenished by leukemic-initiating cells (ICs), which proliferate slowly and are refractory to chemotherapeutic agents. We investigated whether interleukin (IL)-12, an immuno-modulatory cytokine with anti- tumor activity, may target AML blasts (CD45(+)CD33(+)) and populations known to contain leukemia ICs (that is, CD34(+)CD38(-), CD33(+)CD38(+) and CD44(+)CD38(-) cells). We demonstrate for the first time that: i) AML blasts and their CD34(+)CD38(-), CD33(+)CD38(+), CD44(+)CD38(-) subsets express the heterodimeric IL-12 receptor (IL-12R), ii) AML cells injected subcutaneously into NOD/SCID/Il2rg(-/-) (NSG) mice developed a localized tumor mass containing leukemic ICs and blasts that were virtually eliminated by IL-12 treatment, iii) AML cells injected intravenously into NSG mice engrafted within the first month in the spleen, but not in bone marrow or peripheral blood. At this time, IL-12 dramatically dampened AML CD45(+)CD33(+), CD34(+)CD38(-), CD33(+)CD38(+) and CD44(+)CD38(-) populations, only sparing residual CD33(+)CD38(+) cells that did not express IL-12Rβ2. From 30 to 60 days after the initial inoculum, these IL-12-unresponsive cells expanded and metastasized in both control and IL-12-treated NSG mice. Our data indicate that the absence of IL-12Rβ2 in pediatric AML cells favours leukemia progression in NOD/SCID/IL2Rγc-deficient mice.
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Authors | E Ferretti, D Montagna, E Di Carlo, C Cocco, D Ribatti, E Ognio, C Sorrentino, D Lisini, A Bertaina, F Locatelli, V Pistoia, I Airoldi |
Journal | Leukemia
(Leukemia)
Vol. 26
Issue 2
Pg. 225-35
(Feb 2012)
ISSN: 1476-5551 [Electronic] England |
PMID | 21844875
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antigens, CD
- Antigens, Differentiation, Myelomonocytic
- CD33 protein, human
- Cd33 protein, mouse
- Interleukin-12 Receptor beta 2 Subunit
- Sialic Acid Binding Ig-like Lectin 3
- ADP-ribosyl Cyclase 1
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Topics |
- ADP-ribosyl Cyclase 1
(immunology)
- Adolescent
- Adult
- Animals
- Antigens, CD
(immunology)
- Antigens, Differentiation, Myelomonocytic
(immunology)
- Cell Division
- Child
- Child, Preschool
- Disease Progression
- Female
- Flow Cytometry
- Humans
- Infant
- Interleukin-12 Receptor beta 2 Subunit
(metabolism)
- Leukemia, Myeloid, Acute
(immunology, metabolism, pathology)
- Male
- Mice
- Mice, Inbred NOD
- Mice, SCID
- Real-Time Polymerase Chain Reaction
- Sialic Acid Binding Ig-like Lectin 3
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