Project description:This SuperSeries is composed of the following subset Series: GSE24381: Inhibition of BCL6-dependent gene expression in Philadelphia chromosome positive acute lymphoblastic leukemia GSE24404: Recruitment of BCL6 to target genes in Philadelphia chromosome positive acute lymphoblastic leukemia Refer to individual Series
Project description:The two major isoforms of the oncogenic Bcr-Abl tyrosine kinase, p210 and p185, are expressed upon the Philadelphia chromosome translocation. p210 is the hallmark of chronic myelogenous leukemia, whereas p185 occurs in the majority of B-cell acute lymphoblastic leukemia. Differences in protein-protein interactions and activated signaling pathways that may be associated with the different diseases driven by p210 and p185 are unknown. We have performed a quantitative comparative proteomics study of p210 and p185 and found strong differences in the interactome and phosphoproteome. Whereas the AP2 endocytosis complex interacts preferentially with p185, the phosphatase Sts1 is enriched with p210. Stronger activation of STAT5 and ERK1/2 is observed with p210, whereas Lyn is activated by p185. These results were validated in human p210 and p185-positive cell lines. Our findings contribute to a more coherent understanding of Bcr-Abl signaling, mechanisms of oncogenic transformation, resulting disease pathobiology and responses to kinase inhibitors.
Project description:BCR-ABL positive acute lymphoblastic leukemia (ALL) cell survival is strongly dependent on the IRE1α-XBP1 branch of the Unfolded Protein Response (UPR). In the study at hand, we have focused on exploring the link between BCR-ABL1 and IRE1α to better understand whether a simultaneous pharmacological inhibition of both pathways could represent a beneficial therapeutic strategy in Philadelphia positive (Ph+) ALL. Therefore, the effect on the phosphoproteome of two inhibitors (MKC-8866 and Nilotinib) as well as a combination of both compounds was analysed in this study.
Project description:Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL) is a subset of ALL with a high rate of treatment failure. PDGFRB gene fusion is one of the hallmarks of Ph-like ALL. We identified a novel oncogenic PDGFRB fusion gene, NRIP1::PDGFRB, from a pediatric patient with ALL
Project description:The Philadelphia chromosome (Ph) encodes the oncogenic BCR-ABL1 tyrosine kinase, which defines a subset of acute lymphoblastic leukemia (ALL) with a particularly unfavorable prognosis. In this study, the tyrosine kinase inhibitor imatinib was used for pharmacological inhibition of BCR-ABL1. Gene expression profiles of Ph+ ALL cell lines were analyzed in response to imatinib treatment.
