Absence of IL-12Rβ2 in CD33(+)CD38(+) pediatric acute myeloid leukemia cells favours progression in NOD/SCID/IL2RγC-deficient mice.

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.

• 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)

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

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