title: 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.affiliation: Laboratory of Oncology, G. Gaslini Institute, Genova, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Ferretti
authors.forename: D
authors.initials: D
authors.lastname: Montagna
authors.forename: E
authors.initials: E
authors.lastname: Di Carlo
authors.forename: C
authors.initials: C
authors.lastname: Cocco
authors.forename: D
authors.initials: D
authors.lastname: Ribatti
authors.forename: E
authors.initials: E
authors.lastname: Ognio
authors.forename: C
authors.initials: C
authors.lastname: Sorrentino
authors.forename: D
authors.initials: D
authors.lastname: Lisini
authors.forename: A
authors.initials: A
authors.lastname: Bertaina
authors.forename: F
authors.initials: F
authors.lastname: Locatelli
authors.forename: V
authors.initials: V
authors.lastname: Pistoia
authors.forename: I
authors.initials: I
authors.lastname: Airoldi
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000276:immunology*; D000293:Adolescent; D000328:Adult; D000818:Animals; D015703:Antigens, CD / Q000276:immunology*; D015214:Antigens, Differentiation, Myelomonocytic / Q000276:immunology*; D002455:Cell Division; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007223:Infant; D053712:Interleukin-12 Receptor beta 2 Subunit / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D060888:Real-Time Polymerase Chain Reaction; D063268:Sialic Acid Binding Ig-like Lectin 3
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; C571163:CD33 protein, human; C571165:Cd33 protein, mouse; D053712:Interleukin-12 Receptor beta 2 Subunit; D063268:Sialic Acid Binding Ig-like Lectin 3; D051997:ADP-ribosyl Cyclase 1