RESUMO
Kinase signaling fuels growth of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Yet its role in leukemia initiation is unclear and has not been shown in primary human hematopoietic cells. We previously described activating mutations in interleukin-7 receptor alpha (IL7RA) in poor-prognosis "ph-like" BCP-ALL. Here we show that expression of activated mutant IL7RA in human CD34+ hematopoietic stem and progenitor cells induces a preleukemic state in transplanted immunodeficient NOD/LtSz-scid IL2Rγnull mice, characterized by persistence of self-renewing Pro-B cells with non-productive V(D)J gene rearrangements. Preleukemic CD34+CD10highCD19+ cells evolve into BCP-ALL with spontaneously acquired Cyclin Dependent Kinase Inhibitor 2 A (CDKN2A) deletions, as commonly observed in primary human BCP-ALL. CRISPR mediated gene silencing of CDKN2A in primary human CD34+ cells transduced with activated IL7RA results in robust development of BCP-ALLs in-vivo. Thus, we demonstrate that constitutive activation of IL7RA can initiate preleukemia in primary human hematopoietic progenitors and cooperates with CDKN2A silencing in progression into BCP-ALL.
Assuntos
Subunidade alfa de Receptor de Interleucina-7/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Células Precursoras de Linfócitos B/imunologia , Transdução de Sinais/imunologia , Animais , Antígenos CD34/genética , Antígenos CD34/imunologia , Antígenos CD34/metabolismo , Sequência de Bases , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/imunologia , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Expressão Gênica/imunologia , Humanos , Subunidade alfa de Receptor de Interleucina-7/genética , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Células Precursoras de Linfócitos B/metabolismo , RNA-Seq/métodos , Receptores de Citocinas/genética , Receptores de Citocinas/imunologia , Receptores de Citocinas/metabolismo , Transdução de Sinais/genética , Análise de Célula Única/métodos , Transplante HeterólogoRESUMO
Cancer is currently a major threat to public health, being among the principal causes of death to the global population. With carcinogenesis mechanisms, cancer invasion, and metastasis remaining blurred, cancer diagnosis and novel drug delivery approaches should be developed urgently to enable management and treatment. A dream break-through would be a non-invasive instantaneous monitoring of cancer initiation and progression to fast-track diagnosis for timely specialist treatment decisions. These innovations would enhance the established treatment protocols, unlimited by evasive biological complexities during tumorigenesis. It is therefore contingent that emerging and future scientific technologies be equally biased towards such innovations by exploiting the apparent properties of new developments and materials especially nanomaterials. CNCs as nanomaterials have undisputable physical and excellent biological properties that enhanced their interest as biomedical materials. This article therefore highlights CNCs utility in cancer diagnosis and therapy. Their extraction, properties, modification, in-vivo/in-vitro medical applications, biocompatibility, challenges and future perspectives are precisely discussed.
