RESUMO
The transcription factor STAT5 has a critical role in B cell acute lymphoblastic leukemia (B-ALL). How STAT5 mediates this effect is unclear. Here we found that activation of STAT5 worked together with defects in signaling components of the precursor to the B cell antigen receptor (pre-BCR), including defects in BLNK, BTK, PKCß, NF-κB1 and IKAROS, to initiate B-ALL. STAT5 antagonized the transcription factors NF-κB and IKAROS by opposing regulation of shared target genes. Super-enhancers showed enrichment for STAT5 binding and were associated with an opposing network of transcription factors, including PAX5, EBF1, PU.1, IRF4 and IKAROS. Patients with a high ratio of active STAT5 to NF-κB or IKAROS had more-aggressive disease. Our studies indicate that an imbalance of two opposing transcriptional programs drives B-ALL and suggest that restoring the balance of these pathways might inhibit B-ALL.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Linfócitos B , Regulação Neoplásica da Expressão Gênica , Fator de Transcrição Ikaros/genética , Receptores de Células Precursoras de Linfócitos B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Fator de Transcrição STAT5/metabolismo , Tirosina Quinase da Agamaglobulinemia , Animais , Imunoprecipitação da Cromatina , Citometria de Fluxo , Humanos , Fatores Reguladores de Interferon/genética , Camundongos , Reação em Cadeia da Polimerase Multiplex , Subunidade p50 de NF-kappa B/genética , Fator de Transcrição PAX5/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Prognóstico , Proteína Quinase C beta/genética , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais , Taxa de Sobrevida , Transativadores/genéticaRESUMO
The transcription factor signal transducer and activator of transcription 5 (STAT5) is activated by a number of cytokine and growth hormone receptors and plays a key role in the development and function of many organ systems. In this review, we focus on recent discoveries about the role of STAT5 in the development and function of B and T lymphocytes. Of particular interest is the growing appreciation for the function of STAT5 as a transcriptional repressor. Finally, we discuss recent discoveries about the role of STAT5 in transformation of B and T lymphocytes.
Assuntos
Linfócitos B/imunologia , Linfócitos B/metabolismo , Diferenciação Celular/imunologia , Ativação Linfocitária/imunologia , Fator de Transcrição STAT5/fisiologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Linfócitos B/citologia , Humanos , Linfócitos T/citologiaRESUMO
As STAT5 is critical for the differentiation, proliferation, and survival of progenitor B cells, this transcription factor may play a role in acute lymphoblastic leukemia (ALL). Here, we show increased expression of activated signal transducer and activator of transcription 5 (STAT5), which is correlated with poor prognosis, in ALL patient cells. Mutations in EBF1 and PAX5, genes critical for B cell development have also been identified in human ALL. To determine whether mutations in Ebf1 or Pax5 synergize with STAT5 activation to induce ALL, we crossed mice expressing a constitutively active form of STAT5 (Stat5b-CA) with mice heterozygous for Ebf1 or Pax5. Haploinsufficiency of either Pax5 or Ebf1 synergized with Stat5b-CA to rapidly induce ALL in 100% of the mice. The leukemic cells displayed reduced expression of both Pax5 and Ebf1, but this had little effect on most EBF1 or PAX5 target genes. Only a subset of target genes was deregulated; this subset included a large percentage of potential tumor suppressor genes and oncogenes. Further, most of these genes appear to be jointly regulated by both EBF1 and PAX5. Our findings suggest a model whereby small perturbations in a self-reinforcing network of transcription factors critical for B cell development, specifically PAX5 and EBF1, cooperate with STAT5 activation to initiate ALL.