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Exploring the role of IL-7, CK2, and SphK in T-cell acute lymphoblastic leukemia
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A leucemia linfoblástica aguda de linfócitos T (LLA-T) é uma doença hemato oncológica infantil agressiva, de mau prognóstico. Apesar das melhorias significativas no tratamento desta doença, são necessárias novas terapias menos tóxicas. A interleucina-7 (IL-7) e o seu receptor (IL-7R) são essenciais para o normal desenvolvimento e homeostasia dos linfócitos-T, podendo, contudo, contribuir também para a viabilidade e proliferação das células LLA-T e acelerar a progressão da leucemia in vivo. Cerca de 9% dos pacientes LLA-T apresentam mutações de ganho-de-função no IL-7R, conduzindo a sinalização constitutiva e oncogénica. Nesta tese, identificámos STAT5 como elemento essencial para uma eficiente sinalização mediada pela IL-7 em LLA-T, envolvido na inibição de apoptose, aumento do crescimento e proliferação das células leucémicas. Demonstrámos igualmente que a via Jak/STAT5 é um dos principais reguladores da rede trascripcional activada por IL-7, revelando PIM1 como alvo directo e caracterizando o seu papel na transmissão dos sinais pro-sobrevivência e proliferação mediados pela IL-7. Também identificámos a caseína cinase (CK2) e esfingosina cinases (SphK) como moduladores-chave dos sinais induzidos pela IL-7. Demonstrámos que a IL 7 regula positivamente a actividade da CK2 e SphK, sendo que a inibição destas enzimas impede a activação, mediada pela IL-7, das vias de sinalização PI3K/AKT e JAK/STAT, e a consequente promoção de viabilidade e entrada no ciclo celular das células LLA-T. Concluindo, os nossos estudos identificam Jak/STAT5/PIM1 como uma via principal dos sinais mediados pela IL-7, e a CK2 e a SphK como moduladores essenciais da activação das vias pro-sobrevivência e proliferação dependentes da IL-7 em LLA-T. Uma vez que mais de 70% dos pacientes de LLA-T respondem à IL-7 ou possuem mutações de ganho-de-função no IL-7R, as nossas observações abrem novas possibilidades terapêuticas para esta patologia.
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive childhood hematological malignancy. Despite the many improvements made in the treatment of T-ALL, it remains a therapeutic challenge. Novel, less toxic therapies are still needed. Interleukin-7 (IL-7) and its receptor (IL-7R) are essential for normal T-cell development and homeostasis. However, IL-7 can also contribute to the viability and proliferation of T-ALL cells and accelerate leukemia progression in vivo. Moreover, around 9% of T-ALL patients display IL-7R gain-of-function mutations that lead to constitutive and oncogenic signaling. Here, we identified STAT5 as an essential element for efficient IL-7-mediated signaling, involved in preventing apoptosis, and promoting cell growth and proliferation of T-ALL cells. Moreover, we showed that Jak/STAT5 signaling pathway is a major regulator of the transcriptional network downstream of IL-7 stimulation in T-ALL. We demonstrated that PIM1 is a direct STAT5 target, involved in IL-7-mediated pro-survival and proliferative signals in T-ALL. Overall, STAT5 and its transcriptional network are essential for IL-7-mediated survival of T-ALL cells. We also identified casein kinase 2 (CK2) and sphingosine kinases (SphK) as key modulators of IL-7-mediated signaling. IL-7 positively regulates CK2 and SphK activity without significantly affecting their expression. Inhibition of these kinases prevents IL-7-mediated activation of both PI3K/AKT and JAK/STAT pathways, and consequent viability and cell cycle progression of T-ALL cells. In summary, our studies identified Jak/STAT5/PIM1 as a main axis downstream from IL-7 stimulation and CK2 and SphK as essential modulators of IL-7-dependent activation of pro-survival and proliferative pathways in T-ALL. Since more than 70% of T-ALL patients respond to IL-7 or have IL-7R gain-of-function mutations, our observations open new possible therapeutic avenues in this pathology.
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive childhood hematological malignancy. Despite the many improvements made in the treatment of T-ALL, it remains a therapeutic challenge. Novel, less toxic therapies are still needed. Interleukin-7 (IL-7) and its receptor (IL-7R) are essential for normal T-cell development and homeostasis. However, IL-7 can also contribute to the viability and proliferation of T-ALL cells and accelerate leukemia progression in vivo. Moreover, around 9% of T-ALL patients display IL-7R gain-of-function mutations that lead to constitutive and oncogenic signaling. Here, we identified STAT5 as an essential element for efficient IL-7-mediated signaling, involved in preventing apoptosis, and promoting cell growth and proliferation of T-ALL cells. Moreover, we showed that Jak/STAT5 signaling pathway is a major regulator of the transcriptional network downstream of IL-7 stimulation in T-ALL. We demonstrated that PIM1 is a direct STAT5 target, involved in IL-7-mediated pro-survival and proliferative signals in T-ALL. Overall, STAT5 and its transcriptional network are essential for IL-7-mediated survival of T-ALL cells. We also identified casein kinase 2 (CK2) and sphingosine kinases (SphK) as key modulators of IL-7-mediated signaling. IL-7 positively regulates CK2 and SphK activity without significantly affecting their expression. Inhibition of these kinases prevents IL-7-mediated activation of both PI3K/AKT and JAK/STAT pathways, and consequent viability and cell cycle progression of T-ALL cells. In summary, our studies identified Jak/STAT5/PIM1 as a main axis downstream from IL-7 stimulation and CK2 and SphK as essential modulators of IL-7-dependent activation of pro-survival and proliferative pathways in T-ALL. Since more than 70% of T-ALL patients respond to IL-7 or have IL-7R gain-of-function mutations, our observations open new possible therapeutic avenues in this pathology.
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LLA-T sinais da IL-7 Jak/STAT5/PIM1 CK2 SphK T-ALL IL-7 signaling