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1.
Leukemia ; 36(1): 42-57, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34193976

RESUMEN

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype of B-ALL often associated with genetic variants that alter cytokine receptor signaling, including mutations in the interleukin-7 receptor (IL7R). To investigate whether IL7R variants are leukemia-initiating, we built mouse models expressing activated Il7r (aIL7R). B-cell intrinsic aIL7R mice developed spontaneous B-ALL, demonstrating sufficiency of Il7r activating mutations in leukemogenesis. Concomitant introduction of a knock-out allele in the associated adapter protein Lnk (encoded by Sh2b3) or a dominant-negative variant of the transcription factor Ikaros (Ikzf1) increased disease penetrance. The resulting murine leukemias displayed monoclonality and recurrent somatic Kras mutations and efficiently engrafted into immunocompetent mice. Phosphoproteomic analyses of aIL7R leukemic cells revealed constitutive Stat5 signaling and B cell receptor (BCR)-like signaling despite the absence of surface pre-BCR. Finally, in vitro treatment of aIL7R leukemic B-cells with Jak, mTOR, or Syk inhibitors blocked growth, confirming that each pathway is active in this mouse model of IL7R-driven B-ALL.


Asunto(s)
Regulación Leucémica de la Expresión Génica , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Receptores de Interleucina-7/metabolismo , Animales , Apoptosis , Proliferación Celular , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Leucemia-Linfoma Linfoblástico de Células Precursoras B/etiología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Receptores de Interleucina-7/genética , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
2.
J Immunol ; 207(11): 2710-2719, 2021 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-34740959

RESUMEN

The single-nucleotide polymorphism (SNP) rs3184504 is broadly associated with increased risk for multiple autoimmune and cardiovascular diseases. Although the allele is uniquely enriched in European descent, the mechanism for the widespread selective sweep is not clear. In this study, we find the rs3184504*T allele had a strong association with reduced mortality in a human sepsis cohort. The rs3184504*T allele associates with a loss-of-function amino acid change (p.R262W) in the adaptor protein SH2B3, a likely causal variant. To better understand the role of SH2B3 in sepsis, we used mouse modeling and challenged SH2B3-deficient mice with a polymicrobial cecal-ligation puncture (CLP) procedure. We found SH2B3 deficiency improved survival and morbidity with less organ damage and earlier bacterial clearance compared with control mice. The peritoneal infiltrating cells exhibited augmented phagocytosis in Sh2b3 -/- mice with enriched recruitment of Ly6Chi inflammatory monocytes despite equivalent or reduced chemokine expression. Rapid cycling of monocytes and progenitors occurred uniquely in the Sh2b3 -/- mice following CLP, suggesting augmented myelopoiesis. To model the hypomorphic autoimmune risk allele, we created a novel knockin mouse harboring a similar point mutation in the murine pleckstrin homology domain of SH2B3. At baseline, phenotypic changes suggested a hypomorphic allele. In the CLP model, homozygous knockin mice displayed improved mortality and morbidity compared with wild-type or heterozygous mice. Collectively, these data suggest that hypomorphic SH2B3 improves the sepsis response and that balancing selection likely contributed to the relative frequency of the autoimmune risk variant.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/inmunología , Sepsis/inmunología , Proteínas Adaptadoras Transductoras de Señales/genética , Adulto , Animales , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones Congénicos , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Polimorfismo de Nucleótido Simple/genética , Sepsis/genética
3.
J Exp Med ; 215(10): 2485-2496, 2018 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-30194267

RESUMEN

Activated PI3K-delta syndrome (APDS) is an immunodeficiency caused by gain-of-function mutations in PIK3CD. This disease exhibits complex immune phenotypes including increased IgM, recurrent infection, and impaired vaccine responses. To better understand the impact of B cells in this disease, we generated an inducible model of the common APDS mutation (hPIK3CD-E1021K; referred to as aPIK3CD) and intercrossed these mice with B cell-specific Cre models. Mb1-aPIK3CD mice exhibited bone marrow B lymphopenia and, conversely, expansion of the peripheral innate B1a and MZ B cell compartments. aPIK3CD B cells manifest increased pS6 and increased survival at several stages, without alterations in cycling, and baseline increases in plasma cells, natural IgM, and IgG3. Finally, Mb1-aPIK3CD mice exhibited blunted T cell-independent immune responses, and both AID- and CD21-aPIK3CD mice displayed reduced class-switched antibodies following T cell-dependent immunization. Thus, aPIK3CD alters B cell development and function and is counter-productive during immune responses, providing insight into B cell-intrinsic contributions to the APDS phenotype.


Asunto(s)
Mutación con Ganancia de Función , Enfermedades Genéticas Congénitas/inmunología , Inmunidad Innata , Síndromes de Inmunodeficiencia/inmunología , Fosfatidilinositol 3-Quinasas/inmunología , Células Plasmáticas/inmunología , Animales , Fosfatidilinositol 3-Quinasa Clase I/genética , Fosfatidilinositol 3-Quinasa Clase I/inmunología , Activación Enzimática/genética , Activación Enzimática/inmunología , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/patología , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/patología , Ratones , Ratones Noqueados , Fosfatidilinositol 3-Quinasas/genética , Células Plasmáticas/patología , Enfermedades de Inmunodeficiencia Primaria
4.
J Exp Med ; 215(9): 2445-2461, 2018 09 03.
Artículo en Inglés | MEDLINE | ID: mdl-30127060

RESUMEN

Activating mutations in the adapter protein CARD11 associated with diffuse large B cell lymphomas (DLBCLs) are predicted to arise during germinal center (GC) responses, leading to inappropriate activation of NF-κB signaling. Here, we modeled the B cell-intrinsic impact of the L251P activating mutation in CARD11 (aCARD11) on the GC response. Global B cell aCARD11 expression led to a modest increase in splenic B cells and a severe reduction in B1 B cell numbers, respectively. Following T cell-dependent immunization, aCARD11 cells exhibited increased rates of GC formation, resolution, and differentiation. Restriction of aCARD11 to GC B cells similarly altered the GC response and B cell differentiation. In this model, aCARD11 promoted dark zone skewing along with increased cycling, AID levels, and class switch recombination. Furthermore, aCard11 GC B cells displayed increased biomass and mTORC1 signaling, suggesting a novel strategy for targeting aCARD11-driven DLBCL. While aCARD11 potently impacts GC responses, the rapid GC contraction suggests it requires collaboration with events that limit terminal differentiation to promote lymphoma.


Asunto(s)
Linfocitos B/inmunología , Proteínas Adaptadoras de Señalización CARD/inmunología , Diferenciación Celular/inmunología , Centro Germinal/inmunología , Linfoma de Células B Grandes Difuso/inmunología , Diana Mecanicista del Complejo 1 de la Rapamicina/inmunología , Modelos Inmunológicos , Proteínas de Neoplasias/inmunología , Transducción de Señal/inmunología , Animales , Linfocitos B/patología , Proteínas Adaptadoras de Señalización CARD/genética , Diferenciación Celular/genética , Centro Germinal/patología , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Diana Mecanicista del Complejo 1 de la Rapamicina/genética , Ratones , Ratones Transgénicos , Proteínas de Neoplasias/genética , Transducción de Señal/genética
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