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Distinct GAB2 signaling pathways are essential for myeloid and lymphoid transformation and leukemogenesis by BCR-ABL1

ABSTRACT: Tyrosine kinase inhibitors (TKIs) directed against BCR-ABL1, the product of the Philadelphia (Ph) chromosome, have revolutionized treatment of patients with chronic myeloid leukemia (CML). However, acquired resistance to TKIs is a significant clinical problem in CML, and TKI therapy is much less effective against Ph+ B-cell acute lymphoblastic leukemia (B-ALL). BCR-ABL1, via phosphorylated Tyr177, recruits the adapter GAB2 as part of a GRB2/GAB2 complex. We showed previously that GAB2 is essential for BCR-ABL1-evoked myeloid transformation in vitro. Using a genetic strategy and mouse models of CML and B-ALL, we show here that GAB2 is essential for myeloid and lymphoid leukemogenesis by BCR-ABL1. In the mouse model, recipients of BCR-ABL1-transduced Gab2-/- bone marrow failed to develop CML-like myeloproliferative neoplasia. Leukemogenesis was restored by expression of GAB2 but not by GAB2 mutants lacking binding sites for its effectors PI3K or SHP2. GAB2 deficiency also attenuated BCR-ABL1-induced B-ALL, but only the SHP2 binding site was required. The SHP2 and PI3K binding sites were differentially required for signaling downstream of GAB2. Hence, GAB2 transmits critical transforming signals from Tyr177 to PI3K and SHP2 for CML pathogenesis, whereas only the GAB2-SHP2 pathway is essential for lymphoid leukemogenesis. Given that GAB2 is dispensable for normal hematopoiesis, GAB2 and its effectors PI3K and SHP2 represent promising targets for therapy in Ph+ hematologic neoplasms.

ORGANISM(S): Mus musculus

PROVIDER: GSE75615 | GEO | 2016/01/17

SECONDARY ACCESSION(S): PRJNA304742

REPOSITORIES: GEO

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Distinct GAB2 signaling pathways are essential for myeloid and lymphoid transformation and leukemogenesis by BCR-ABL1

Project description:Tyrosine kinase inhibitors (TKIs) directed against BCR-ABL1, the product of the Philadelphia (Ph) chromosome, have revolutionized treatment of patients with chronic myeloid leukemia (CML). However, acquired resistance to TKIs is a significant clinical problem in CML, and TKI therapy is much less effective against Ph+ B-cell acute lymphoblastic leukemia (B-ALL). BCR-ABL1, via phosphorylated Tyr177, recruits the adapter GAB2 as part of a GRB2/GAB2 complex. We showed previously that GAB2 is essential for BCR-ABL1-evoked myeloid transformation in vitro. Using a genetic strategy and mouse models of CML and B-ALL, we show here that GAB2 is essential for myeloid and lymphoid leukemogenesis by BCR-ABL1. In the mouse model, recipients of BCR-ABL1-transduced Gab2-/- bone marrow failed to develop CML-like myeloproliferative neoplasia. Leukemogenesis was restored by expression of GAB2 but not by GAB2 mutants lacking binding sites for its effectors PI3K or SHP2. GAB2 deficiency also attenuated BCR-ABL1-induced B-ALL, but only the SHP2 binding site was required. The SHP2 and PI3K binding sites were differentially required for signaling downstream of GAB2. Hence, GAB2 transmits critical transforming signals from Tyr177 to PI3K and SHP2 for CML pathogenesis, whereas only the GAB2-SHP2 pathway is essential for lymphoid leukemogenesis. Given that GAB2 is dispensable for normal hematopoiesis, GAB2 and its effectors PI3K and SHP2 represent promising targets for therapy in Ph+ hematologic neoplasms. RNA-Seq expression profiling of 6 mouse bone marrow samples: 3 GAB2 WT (+/+) and 3 GAB2 NULL (-/-)

2016-01-17 | E-GEOD-75615 | biostudies-arrayexpress

SHP2 Is Required for BCR-ABL1-Induced Hematologic Neoplasms

Project description:BCR-ABL1-targeting tyrosine kinase inhibitors (TKIs) have revolutionized treatment of Philadelphia chromosome-positive (Ph+) hematologic neoplasms. Nevertheless, acquired TKI resistance remains a major problem in chronic myeloid leukemia (CML), and TKIs are less effective against Ph+ B-cell acute lymphoblastic leukemia (B-ALL). GAB2, a scaffolding adaptor that binds and activates SHP2, is essential for leukemogenesis by BCR-ABL1, and a GAB2 mutant lacking SHP2 binding cannot mediate leukemogenesis. Using a genetic loss-of-function approach and bone marrow transplantation (BMT) models for CML and BCR-ABL1+ B-ALL, we show that SHP2 is required for BCR-ABL1-evoked myeloid and lymphoid neoplasia. Ptpn11 deletion impairs initiation and maintenance of CML-like myeloproliferative neoplasm, and compromises induction of BCR-ABL1+ B-ALL. SHP2, and specifically, its SH2 domains, PTP activity and C-terminal tyrosines, is essential for BCR-ABL1+, but not WT, pre-B cell proliferation. The MEK/ERK pathway is regulated by SHP2 in WT and BCR-ABL1+ pre-B cells, but is only required for the proliferation of BCR-ABL1+ cells. SHP2 is required for SRC family kinase (SFK) activation only in BCR-ABL1+ pre-B cells. RNAseq reveals distinct SHP2-dependent transcriptional programs in BCR-ABL1+ and WT pre-B cells. Our results suggest that SHP2, via SFKs and ERK, represses MXD3/4 to facilitate a MYC-dependent proliferation program in BCR-ABL1-transformed pre-B cells.

2017-06-06 | GSE99656 | GEO

Neddylation Status Determines the Therapeutic Sensitivity of BCR-ABL1-targeting Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia

Project description:BCR-ABL1-targeting tyrosine kinase inhibitors (TKIs) dominate the treatment of chronic myeloid leukemia (CML) over the past decades. In this study, we reported an unexpected role of neddylation inhibitors in desensitizing the therapeutic efficacy of BCR-ABL1-targeting TKIs in CML. Unlike their function in reducing drug resistance in many solid tumors, we revealed that neddylation inhibitors counteracted the cytotoxicity of TKIs against CML cells, both in cellular experiments and in animal model. Conversely, neddylation agonist sensitized the function of TKIs. RNA sequencing data revealed that neddylation inhibitor reversed the transcriptomic changes induced by TKI. Co-immunoprecipitation (co-IP) assay identified ABL1 kinase domain as a novel substrate for neddylation. Furthermore, an artificial intelligence (AI) 3-Dimensional spatial structure binding technology was employed to predict the impact of neddylation on the structure of ABL1 kinase domain. Finally, we provided potential evidence showing that TKI therapy decreased the expression of neddylation enzymes in the bone marrow of CML patients. Hence, our study offers new insights into the post-translational modification (PTM)-mediated drug resistance, and highlights the potential clinical benefits of neddylation agonists in improving the responsiveness of BCR-ABL1 TKIs in CML.

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Targeting FLT3-TAZ Signaling to Suppress Drug Resistance in Blast Crisis Chronic Myeloid Leukemia

Project description:Although the development of tyrosine kinase inhibitors (TKIs), including BCR-ABL1 targeted therapies, rendered chronic myeloid leukemia (CML) a manageable condition, acquisition of drug resistance during blast crisis (BC) progression remains a critical challenge. Here, we elucidate the significance of FLT3 signaling in the acquisition of drug resistance in BC-CML. Mechanistically, FLT3 expression in CML cells activated FLT3-JAK-STAT3-TAZ-TEAD-CD36 pathway, which conferred resistance to wide range of tyrosine kinase inhibitors (TKIs). Remarkably, a subgroup of BC-CML patients who expressed FLT3 showed strong correlation with the prognostic factors of CML independent of recurrent BCR-ABL1 mutations. We demonstrate that combining FLT3 inhibitors with BCR-ABL1 targeted therapies or single treatment with ponatinib can overcome drug resistance and promote cell death in patient-derived FLT3+ BC-CML cells and mouse xenograft models. Our findings reveal the mechanism of FLT3-mediated drug resistance in BC progression and suggest the inclusion of FLT3 as a therapeutic target for this defined group of patients.

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Effect of Imatinib on chronic myelogenous leukemia

Project description:The Philadelphia chromosome (Ph) encodes the oncogenic BCR-ABL1 tyrosine kinase, which is present in almost every patient with chronic myeloid leukemia. In this study, the tyrosine kinase inhibitor Imatinib was used for pharmacological inhibition of BCR-ABL1. Gene expression profiles of CML cell lines were analyzed in response to Imatinib treatment.

2010-10-10 | GSE24493 | GEO

SFPQ-ABL1 and BCR-ABL1 utilise different signalling networks to drive B-cell acute lymphoblastic leukaemia

Project description:Philadelphia-like (Ph-like) acute lymphoblastic leukaemia (ALL) is a high-risk subtype of B-cell ALL characterised by a gene expression profile resembling Philadelphia Chromosome positive ALL (Ph+ ALL) in the absence of BCR-ABL1. Tyrosine kinase activating fusions, some involving ABL1, are recurrent drivers of Ph-like ALL and are targetable with tyrosine kinase inhibitors (TKIs). We identified a rare instance of SFPQ-ABL1 in a child with Ph-like ALL. SFPQ-ABL1 expressed in cytokine-dependent cell lines was sufficient to transform cells which were sensitive to ABL1-targeting TKIs. In contrast to BCR-ABL1, SFPQ-ABL1 localised to the nuclear compartment and was a weaker driver of cellular proliferation. Phosphoproteomics analysis showed upregulation of cell cycle, DNA replication and spliceosome pathways, and downregulation of signal transduction pathways, including ErbB, NF-kappa B, VEGF, and MAPK signalling in SFPQ-ABL1-, compared to BCR-ABL1-expressing cells. SFPQ-ABL1 expression did not activate PI3K/AKT signalling and was associated with phosphorylation of G2/M cell cycle proteins. SFPQ-ABL1 was sensitive to navitoclax and S-63845 and promotes cell survival through upregulation of Mcl-1 and Bcl-xL. SFPQ-ABL1 has functionally distinct mechanisms by which it drives ALL, including subcellular localisation, proliferative capacity, and activation of cellular pathways, highlighting the role that fusion partners have in mediating the function of ABL1 fusions.

2022-05-20 | PXD028925 | Pride

Concomitant inhibition of the thioredoxin system and non-homologous DNA repair potently sensitizes Philadelphia-positive lymphoid leukemia to tyrosine kinase inhibitors

Project description:BCR-ABL1 gene fusion is an essential driver lesion in both chronic myeloid leukemia (CML) and Philadelphia-positive (Ph+) B-cell acute lymphoblastic leukemia (B-ALL). While tyrosine kinase inhibitors (TKIs) cure up to 95% of CML patients, 50 % of Ph+ B-ALL cases do not respond to treatment or relapse. This calls for new therapeutic approaches for Ph+ B-ALL. Dysregulated redox homeostasis manifested by the increased reactive oxygen species (ROS) levels and the upregulation of the thioredoxin (TXN) antioxidant system has been previously shown in B-ALL. Pharmacological inhibition of the TXN system with auranofin (AUR) efficiently kills B-ALL cells, indicating that the TXN system plays a major role in maintaining redox homeostasis in B-ALL cells. Here we show that peroxiredoxin-1 (PRDX1), one of the enzymes of the TXN system responsible for scavenging H2O2, is upregulated in Ph+ lymphoid as compared to Ph+ myeloid cells. The genomic knockout of PRDX1 negatively affects the viability of Ph+ B-ALL cells and sensitizes them to TKIs, while no such effects occur in myeloid cells. By analyzing global changes in gene expression in PRDX1-deficient cells treated with imatinib we discover non-homologous end-joining (NHEJ) DNA repair pathways as a novel vulnerability of Ph+ B-ALL cells. Accordingly, pharmacologic inhibition of the TXN system diminishes the viability of Ph+ B-ALL cells and enhances their sensitivity to TKIs and NHEJ inhibitors. Finally, we propose a novel combination of TKIs, TXN inhibitors, and NHEJ inhibitors as a potential therapeutic approach for the treatment of Ph+ B-ALL.

2024-03-01 | GSE221906 | GEO

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Project description:Tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL1 fusion tyrosine kinase have revolutionized the treatment of chronic myeloid leukemia (CML). However, the development of TKI resistance and the subsequent transition from the chronic phase (CP) to blast crisis (BC) threaten CML patients. Accumulating evidence suggests that translational control is crucial for cancer development and progression. Here, we performed high throughput CRISPR/Cas9 screening and identified poly(A) binding protein cytoplasmic 1 (PABPC1) as a driver for CML-BC progression. PABPC1 preferentially improved the translation efficiency of multiple leukemogenic mRNAs with long and highly structured 5' untranslated regions, including BCR-ABL1 and its TKI-resistant mutants, through forming biomolecular condensates. Inhibiting PABPC1 significantly suppressed CML cell proliferation and attenuated disease progression, but did not affect normal hematopoiesis seriously. More importantly, we identified two novel PABPC1 inhibitors, 1,10-Phen and ML324, which inhibited BC progression and overcame TKI resistance in murine and human CML. Overall, our work identified PABPC1 as a selective translation enhancing factor in CML-BC, the genetic or pharmacological inhibition of which overcame TKI resistance and suppressed BC progression in CML.

2024-03-01 | GSE198142 | GEO

Whole transcriptome sequencing for wild type and IRAIN over-expression K562 cells

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2024-04-13 | GSE263645 | GEO

BCR/ABL1-Dependent Transcriptional Response Reveals Enrichment for Genes Involved in Negative Feedback Regulation

Project description:Philadelphia (Ph) chromosome-positive leukemia is characterized by the BCR/ABL1 fusion protein that affects a wide range of signal transduction pathways. The knowledge about its downstream target genes is, however, still quite limited. To identify novel BCR/ABL1-regulated genes we used global gene expression profiling of several Ph-positive and Ph-negative cell lines treated with imatinib. Following imatinib treatment, the Ph-positive cells showed decreased growth, viability, and reduced phosphorylation of BCR/ABL1 and STAT5. In total, 142 genes were identified as being dependent on BCR/ABL1-mediated signaling, mainly including genes involved in signal transduction, e.g. the JAK/STAT, MAPK, TGFB and insulin signaling pathways, and in regulation of metabolism. Interestingly, BCR/ABL1 was found to activate several genes involved in negative feedback regulation (CISH, SOCS2, SOCS3, PIM1, DUSP6, and TNFAIP3), which may act to indirectly suppress the tumor promoting effects exerted by BCR/ABL1. In addition, several genes identified as deregulated upon BCR/ABL1 expression could be assigned to the TGFB and NFkB signaling pathways, as well as to reflect the metabolic adjustments needed for rapidly growing cells. Apart from providing important pathogenetic insights into BCR/ABL1-mediated leukemogenesis, the present study also provides a number of pathways/individual genes that may provide attractive targets for future development of targeted therapies. Keywords: global gene expression profiling, Ph chromosome, BCR/ABL1, imatinib mesylate

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