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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

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.

2023-11-15 | GSE226360 | GEO

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

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

Project description:The development of tyrosine kinase inhibitors (TKIs) has revolutionarily increased the overall survival of patients with chronic myeloid leukemia (CML). However, drug resistance remains a major obstacle. Here, we demonstrated that a BCR-ABL1-independent long non-coding RNA, IRAIN, is constitutively expressed at low levels in CML, resulting in imatinib resistance. IRAIN knockdown decreased the sensitivity of CD34+ CML blasts and cell lines to imatinib, whereas IRAIN overexpression significantly increased sensitivity. Mechanistically, IRAIN downregulates CD44, a membrane receptor favorably affecting TKI resistance, by binding to the nuclear factor kappa B subunit p65 to reduce the expression of p65 and phosphorylated p65. Therefore, the demethylating drug decitabine, which upregulates IRAIN, combined with imatinib, formed a dual therapy strategy which can be applied to CML with resistance to TKIs.

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

2008-02-01 | GSE10283 | GEO

Targeting PABPC1 suppresses chronic myeloid leukemia disease progression by controlling BCR-ABL1 translation

Project description:PABPC1 mediated protein synthesis control might be important for chronic myeloid leukemia (CML) disease progression. Here, we use the PABPC1 enhanced cross-linking and immunoprecipitation sequencing (eCLIP-seq) to capture PABPC1 directly bound RNAs as well as the ribosome profiling (Ribo-seq) to examine the ribosome protected mRNA fragments in control and PABPC1 silenced K562 cells. We integrated the eCLIP-seq and Ribo-seq data and found that 1496 out of the 6840 PABPC1 directly bound genes, significantly reduced their translation efficiency in PABPC1 silenced K562 cells. Strikingly, the 1496 genes with reduced translational efficiency enriched significant numbers of leukemogenesis oncogenes, such as BCR-ABL1, RPL22, SKP1, and MYCBP. Among them, BCR-ABL1 mRNA translation was the most vigorous, which was also most influenced by PABPC1. Furthermore, we found that PABPC1 inhibition significantly suppressed the BCR-ABL1 downstream gene network in K562 cells (q value<0.001), indicating that BCR-ABL1 might be one of the main targets of PABPC1 in K562 cells.

2024-03-01 | GSE198142 | GEO

Single cell multi-omics analysis of chronic myeloid leukemia links cellular heterogeneity to therapy response

Project description:The advent of tyrosine kinase inhibitors (TKIs) as treatment of Chronic Myeloid Leukemia (CML) is a paradigm in molecularly targeted cancer therapy. Nonetheless, TKI insensitive leukemia stem cells (LSCs) persist in most patients, even after years of treatment. Here, we used cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) to generate high-resolution single cell multiomics maps from CML patients stratified according to molecular response (BCR-ABL IS %) following 12 months of TKI therapy. Simultaneous measurement of global gene expression profiles together with >40 surface markers from the same cells revealed that each patient harbored a unique composition of stem and progenitor cells at diagnosis demonstrating that cellular heterogeneity is a hallmark of CML. The patients with treatment failure at 12 months of therapy had markedly higher abundance of molecularly defined primitive cells at diagnosis compared to the optimal responders. The multi-modal feature landscape enabled visualization of the primitive fraction as a mix of Lin-CD34+38-/low BCR-ABL1+ LSCs and BCR-ABL1- HSCs in variable ratio across patients and guided their prospective isolation by a combination of CD26 and CD35 cell surface markers.

2024-01-17 | GSE236233 | GEO

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