Alterations of Gab2 signalling complexes in imatinib and dasatinib treated chronic myeloid leukaemia cells

Halbach, Sebastian; Rigbolt, Kristoffer; Wöhrle, Franziska U.; Diedrich, Britta; Gretzmeier, Christine; Brummer, Tilman; Dengjel, Jörn

doi:10.1186/1478-811x-11-30

Cited by 18 publications

(13 citation statements)

References 63 publications

(124 reference statements)

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“…The study of proteome-networks is relatively untapped in CML (although elegant examples do exist, [186,187]), making this an attractive area of interest to improve the knowledge of CML biology. The same can be said of non-coding RNA (ncRNA) involvement in CML.…”

Section: Discussionmentioning

confidence: 99%

Natural course and biology of CML

2015

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Chronic myeloid leukaemia (CML) is a myeloproliferative disorder arising in the haemopoietic stem cell (HSC) compartment. This disease is characterised by a reciprocal t(9;22) chromosomal translocation, resulting in the formation of the Philadelphia (Ph) chromosome containing the BCR-ABL1 gene. As such, diagnosis and monitoring of disease involves detection of BCR-ABL1. It is the BCR-ABL1 protein, in particular its constitutively active tyrosine kinase activity, that forges the pathogenesis of CML. This aberrant kinase signalling activates downstream targets that reprogram the cell to cause uncontrolled proliferation and results in myeloid hyperplasia and 'indolent' symptoms of chronic phase (CP) CML. Without successful intervention, the disease will progress into blast crisis (BC), resembling an acute leukaemia. This advanced disease stage takes on an aggressive phenotype and is almost always fatal. The cell biology of CML is also centred on BCR-ABL1. The presence of BCR-ABL1 can explain virtually all the cellular features of the leukaemia (enhanced cell growth, inhibition of apoptosis, altered cell adhesion, growth factor independence, impaired genomic surveillance and differentiation). This article provides an overview of the clinical and cell biology of CML, and highlights key findings and unanswered questions essential for understanding this disease.

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Section: Discussionmentioning

confidence: 99%

Natural course and biology of CML

2015

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“…These findings suggest that the Gab2-SHP2 axis may be exploited as a novel modulator of TKI sensitivity in CML and as a potential therapeutic target in TKI-resistant disease. Notably, a previous study demsontrated that, at equimolar concentrations, dasatinib is more effective in preventing Gab2 tyrosine and serine/threonine phosphorylation, compared with imatinib, suggesting that dasatinib may be an alterative in the clinical therapy of CML ( 64 ).…”

Section: Gab2 In Cancermentioning

confidence: 99%

Structure and function of Gab2 and its role in cancer (Review)

Ding

Feng

et al. 2015

Molecular Medicine Reports

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The docking proteins of the Grb-associated binder (Gab) family transduce cellular signals between receptors and intracellular downstream effectors, and provide a platform for protein-protein interactions. Gab2, a key member of the Gab family of proteins, is involved in the amplification and integration of signal transduction, evoked by a variety of extracellular stimuli, including growth factors, cytokines and antigen receptors. Gab2 protein lacks intrinsic catalytic activity; however, when phosphorylated by protein-tyrosine kinases (PTKs), Gab2 recruits several Src homology-2 (SH2) domain-containing proteins, including the SH2-containing protein tyrosine phosphatase 2 (SHP2), the p85 subunit of phosphoinositide-3 kinase (PI3K), phospholipase C-γ (PLCγ)1, Crk, and GC-GAP. Through these interactions, the Gab2 protein triggers various downstream signal effectors, including SHP2/rat sarcoma viral oncogene/RAF/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase and PI3K/AKT, involved in cell growth, differentiation, migration and apoptosis. It has been previously reported that aberrant Gab2 and/or Gab2 signaling is closely associated with human tumorigenesis, particularly in breast cancer, leukemia and melanoma. The present review aimed to focus on the structure and effector function of Gab2, its role in cancer and its potential for use as an effective therapeutic target.

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“…In addition, about 40 % of resistances are Bcr-Abl mutation-independent [ 5 ] and still ill-defined at the molecular level. These resistances are often caused by aberrant signaling of Bcr-Abl effectors such as the docking protein Gab2 [ 6 – 8 ] or the Src kinase Lyn [ 9 ] (Fig. 1a ).…”

Section: Resultsmentioning

confidence: 99%

“…We also provided several lines of evidence that this docking protein is increasingly expressed in myeloid cells from patients with TKI-refractory disease [ 7 ] or blast crisis [ 22 ], a stage known for its insensitivity to Bcr-Abl inhibitors. Therefore, we tested SF and AX in K562 cells with conditional Gab2 overexpression [ 7 , 8 ]. As observed previously [ 7 ], overexpression of Gab2 conferred resistance towards IM, DST and NL (Fig.…”

Section: Resultsmentioning

confidence: 99%

Axitinib and sorafenib are potent in tyrosine kinase inhibitor resistant chronic myeloid leukemia cells

Halbach

Gretzmeier

et al. 2016

Cell Commun Signal

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BackgroundChronic myeloid leukemia (CML) is driven by the fusion kinase Bcr-Abl. Bcr-Abl tyrosine kinase inhibitors (TKIs), such as imatinib mesylate (IM), revolutionized CML therapy. Nevertheless, about 20 % of CMLs display primary or acquired TKI resistance. TKI resistance can be either caused by mutations within the Bcr-Abl kinase domain or by aberrant signaling by its effectors, e.g. Lyn or Gab2. Bcr-Abl mutations are frequently observed in TKI resistance and can only in some cases be overcome by second line TKIs. In addition, we have previously shown that the formation of Gab2 complexes can be regulated by Bcr-Abl and that Gab2 signaling counteracts the efficacy of four distinct Bcr-Abl inhibitors. Therefore, TKI resistance still represents a challenge for disease management and alternative therapies are urgently needed.FindingsUsing different CML cell lines and models, we identified the clinically approved TKIs sorafenib (SF) and axitinib (AX) as drugs overcoming the resistance mediated by the Bcr AblT315I mutant as well as the one mediated by Gab2 and LynY508F. In addition, we demonstrated that AX mainly affects the Bcr-Abl/Grb2/Gab2 axis, whereas SF seems to act independently of the fusion kinase and most likely by blocking signaling pathways up- and downstream of Gab2.ConclusionWe demonstrate that SF and AX show potency in various and mechanistically distinct scenarios of TKI resistance, including Bcr-AblT315I as well as Lyn- and Gab2-mediated resistances. Our data invites for further evaluation und consideration of these inhibitors in the treatment of TKI resistant CML.Electronic supplementary materialThe online version of this article (doi:10.1186/s12964-016-0129-y) contains supplementary material, which is available to authorized users.

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Alterations of Gab2 signalling complexes in imatinib and dasatinib treated chronic myeloid leukaemia cells

Cited by 18 publications

References 63 publications

Natural course and biology of CML

Natural course and biology of CML

Structure and function of Gab2 and its role in cancer (Review)

Axitinib and sorafenib are potent in tyrosine kinase inhibitor resistant chronic myeloid leukemia cells

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