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:T-cell acute lymphoblastic leukemia is an aggressive hematologic tumor with fewer treatment strategies. Dasatinib, an FDA-approved tyrosine kinase inhibitor applied in chronic myelogenous leukemia and acute lymphoblastic leukemia with Philadelphia chromosome-positive has been utilized in T-ALL for cure but the clinical outcomes are not satisfied, calling for further investigation on the mechanism and potential combinations to overcome resistance. In this study, we performed a genome-wide CRISPR-Cas9 screening and identified the MAPK pathway as an essential regulator of sensitivity to dasatinib. Then we confirmed that the inhibition of the MAPK pathway by dabrafenib could sensitize T-ALL cells to dasatinib in vitro and reveal the underlying mechanism by RNA sequencing. Together, we put forward a promising combining strategy for T-ALL.
Project description:Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a distinct subtype of B-ALL, exhibiting a kinase-activated gene expression profile similar to Philadelphia chromosome-positive (Ph+) ALL, yet lacking the BCR::ABL fusion. Despite the identification of numerous genetic aberrations and chromosomal rearrangements, particularly those involving the ABL-class or CRLF2/JAK pathways, as drivers and therapeutic targets, the genetic diversity and underlying pathogenic mechanisms of Ph-like ALL remain incompletely understood, posing challenges for diagnosis and treatment. Here, we identified a novel JAK2 fusion, ZBTB5::JAK2, in a Ph-like ALL patient, accompanied by a frequent KRAS12D mutation. Single-cell RNA sequencing (scRNA-seq) analysis suggests that the cell population with both high JAK2 and RAS signals may represent the leukemia stem cells in this patient.
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.
