RESUMO
The specific niche adaptations that facilitate primary disease and Acute Lymphoblastic Leukaemia (ALL) survival after induction chemotherapy remain unclear. Here, we show that Bone Marrow (BM) adipocytes dynamically evolve during ALL pathogenesis and therapy, transitioning from cellular depletion in the primary leukaemia niche to a fully reconstituted state upon remission induction. Functionally, adipocyte niches elicit a fate switch in ALL cells towards slow-proliferation and cellular quiescence, highlighting the critical contribution of the adipocyte dynamic to disease establishment and chemotherapy resistance. Mechanistically, adipocyte niche interaction targets posttranscriptional networks and suppresses protein biosynthesis in ALL cells. Treatment with general control nonderepressible 2 inhibitor (GCN2ib) alleviates adipocyte-mediated translational repression and rescues ALL cell quiescence thereby significantly reducing the cytoprotective effect of adipocytes against chemotherapy and other extrinsic stressors. These data establish how adipocyte driven restrictions of the ALL proteome benefit ALL tumours, preventing their elimination, and suggest ways to manipulate adipocyte-mediated ALL resistance.
Assuntos
Adipócitos/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Células 3T3-L1 , Adulto , Animais , Biópsia , Medula Óssea/patologia , Linhagem da Célula , Sobrevivência Celular , Humanos , Camundongos , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Proteoma/metabolismo , Estresse Fisiológico , Análise de Sobrevida , Adulto JovemAssuntos
Anemia/diagnóstico , Anemia/etiologia , Transplante de Rim , Doença Aguda , Adulto , Anemia Aplástica/diagnóstico , Anemia Aplástica/etiologia , Anemia Aplástica/imunologia , Feminino , Humanos , Hospedeiro Imunocomprometido/imunologia , Transplante de Rim/efeitos adversos , Infecções por Parvoviridae/diagnóstico , Infecções por Parvoviridae/etiologia , Infecções por Parvoviridae/imunologiaAssuntos
Adenoviridae/efeitos dos fármacos , Infecções por Adenovirus Humanos/tratamento farmacológico , Conjuntivite Viral/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Adenoviridae/isolamento & purificação , Adenoviridae/patogenicidade , Infecções por Adenovirus Humanos/etiologia , Adulto , Antivirais/uso terapêutico , Cidofovir , Conjuntivite Viral/etiologia , Citosina/análogos & derivados , Citosina/uso terapêutico , Humanos , Masculino , Organofosfonatos/uso terapêutico , Transplante Homólogo/efeitos adversosRESUMO
Idiopathic myelofibrosis (IMF) is a clonal disorder resulting from the proliferation of aberrant hematopoietic stem cells. Conventional treatment is unsatisfactory, and with the exception of supportive blood transfusions, none of the standard therapies have been shown to confer a survival advantage. Allogeneic stem cell transplantation represents the only treatment modality with proven curative potential. Myeloablative conditioning regimens are associated with high transplant-related mortality, particularly in the elderly, making most patients with IMF ineligible for this treatment. Strategies using reduced intensity conditioning regimes have allowed application of allogeneic transplantation to a broader range of patients and a number of recent reports have demonstrated potential efficacy.
