Progenitor B cell acute lymphoblastic leukemia (B-ALL) is the most common form of childhood cancer. New therapies have substantially improved the prognosis of this type of cancer, yet relapsed B-ALL remains a leading cause of death in children and young adults. Thus, B-ALL remains a significant health challenge. Currently, activation of the JAK/STAT5 pathway is strongly implicated in the development of B-ALL. Likewise, genes encoding a network of transcription factors required for B cell development, including IKZF1, PAX5, and EBF1, are frequently expressed at lower levels in B-ALL due to deletions in one of the alleles encoding these transcription factors. Our lab has shown that STAT5 activation cooperates with defects in the pre-BCR signaling pathway, including PAX5, EBF1, PU.1, IRF4, and IKAROS (collectively referred to as PEPII factors hereafter) to initiate transformation. Therefore, these findings demonstrated that proper balance between STAT5 activation and PEPII factors is important for entraining normal B cell differentiation and preventing B cell transformation. One key question that emerges from these results is how STAT5 activation can alter target gene expression. Our data suggests that active phosphorylated STAT5 can bind to target genes and both activate key oncogenes while repressing tumor suppressor genes. However, the mechanism by which this occurs remains unclear. Based on previous studies and preliminary data, STAT5 can associate with co-activators, such as EP300 and CREBBP, and with co-repressors, such as NCOR1 and NCOR2. I hereby propose that the recruitment of EP300 but not CREBBP is critical for STAT5 to induce transcription of key oncogenes. I further propose that the interaction of STAT5 with the NCOR1 and NCOR2 repressor complex is required for STAT5- dependent repression of tumor suppressor genes. Thus, my central hypothesis is that a proper STAT5 transcriptional network is required for promoting normal B cell development and that perturbation of this network can lead to B cell transformation. These hypotheses will be tested in the following two specific aims (1) Establish the mechanism by which STAT5 regulates the transcription of key oncogenes, and (2) Establish how STAT5 represses transcription of key tumor suppressor genes in progenitor B cell leukemia. The completion of these aims will further advance our understanding of how STAT5 both activates and represses transcription and how subsequent perturbation of these functions can lead to transformation in B-ALL.
The transcription factor STAT5 plays an important role in B cell leukemia. STAT5 turns on genes that help cells divide and turns off genes that stop this process. The studies proposed in this application will elucidate how STAT5 regulates expression of these genes and thereby identify potential targets for future pharmaceutical intervention.
