Receptor Tyrosine Kinases: Translocation Partners in Hematopoietic Disorders

Nelson, Katelyn N.; Peiris, Malalage N.; Meyer, April N.; Siari, Asma; Donoghue, Daniel J.

doi:10.1016/j.molmed.2016.11.002

Cited by 30 publications

(31 citation statements)

References 126 publications

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“…Exon 4 of BCR has been found fused to exon 9 of FGFR1, with the RhoGEF domain in BCR partially intact in this fusion [34]. This fusion displays predominantly cytoplasmic localization, and the kinase domain of FGFR1 becomes constitutively activated, leading to the activation of STAT3, STAT5, AKT, MAPK, as well as IL-3 independent growth of Ba/F3 cells (Figure 2) [5]. Interestingly, similar to all other oncogenic BCR fusions, BCR-FGFR1 also retains the coiled-coil dimerization domain of BCR.…”

Section: Bcr: the Philandering Partnermentioning

confidence: 99%

“…PDGFRs consist of 5 immunoglobin like/ligand binding domains, a juxtamembrane domain, a WW domain, as well as a kinase domain [41, 42]. Similar to other RTKs, upon ligand binding, PDGFR undergoes receptor dimerization, autophosphorylation, thereby activating downstream pathways including RAS, and JAK/STAT pathways [5]. Previous studies have shown that the WW domain, containing two conserved tryptophan residues, serves an autoinhibitory role in the juxtamembrane domain.…”

Section: Bcr: the Philandering Partnermentioning

confidence: 99%

“…Identified chromosomal translocations are numerous and varied, many of which produce a translatable fusion protein with oncogenic potential. However, a common theme amongst these fusions is the contribution of a dimerization domain by a partner gene, often fused to a kinase [5]. Arguably the most well studied oncogenic fusion, breakpoint cluster region-Abelson murine leukemia viral oncogene 1 (BCR-ABL), discovered in 1960 and found in 95% of chronic myeloid leukemia cases (CML), is the archetype of this theme.…”

Section: Introduction: Chromosomal Translocations In Cancermentioning

confidence: 99%

“…The BCR-ABL translocation is thus referred to as the Philadelphia chromosome, and resulting leukemias are referred to as Ph+ leukemias. Since its original discovery as part of the Philadelphia chromosome, BCR has been identified fused to multiple tyrosine kinases, including FGFR1, PDGFRA, RET, and JAK2 in hematopoietic malignancies [5]. Yet, the underlying reason behind the commonality of BCR as a fusion partner is not well understood.…”

Section: Introduction: Chromosomal Translocations In Cancermentioning

confidence: 99%

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BCR: a promiscuous fusion partner in hematopoietic disorders

Peiris

Donoghue

2019

Oncotarget

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Considerable advances have been made in our understanding of the molecular basis of hematopoietic cancers. The discovery of the BCR-ABL fusion protein over 50 years ago has brought about a new era of therapeutic progress and overall improvement in patient care, mainly due to the development and use of personalized medicine and tyrosine kinase inhibitors (TKIs). However, since the detection of BCR-ABL, BCR has been identified as a commonly occurring fusion partner in hematopoietic disorders. BCR has been discovered fused to additional tyrosine kinases, including: Fibroblast Growth Factor Receptor 1 (FGFR1), Platelet-derived Growth Factor Receptor Alpha (PDGFRA), Ret Proto-Oncogene (RET), and Janus Kinase 2 (JAK2). While BCR translocations are infrequent in hematopoietic malignancies, clinical evidence suggests that patients who harbor these mutations benefit from TKIs and additional personalized therapies. The improvement of further methodologies for characterization of these fusions is crucial to determine a patient’s treatment regimen, and optimal outcome. However, potential relapse and drug resistance among patients’ highlights the need for additional treatment options and further understanding of these oncogenic fusion proteins. This review explores the mechanisms behind cancer progression of these BCR oncogenic fusion proteins, comparing their similarities and differences, examining the significance of BCR as a partner gene, and discussing current treatment options for these translocation-induced hematopoietic malignancies.

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Section: Bcr: the Philandering Partnermentioning

confidence: 99%

Section: Bcr: the Philandering Partnermentioning

confidence: 99%

Section: Introduction: Chromosomal Translocations In Cancermentioning

confidence: 99%

Section: Introduction: Chromosomal Translocations In Cancermentioning

confidence: 99%

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BCR: a promiscuous fusion partner in hematopoietic disorders

Peiris

Donoghue

2019

Oncotarget

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“…Numerous oncogenic ALK variants have since been identified (3). ALK fusion proteins have been described in many different tumor types, including inflammatory myofibroblastic tumors, nonsmall cell lung cancer, and diffuse large-B cell lymphomas (4,5). The full-length ALK receptor is activated by the ligands ALKAL1 (also known as FAM150A or AUG-) and ALKAL2 (also known as FAM150B or AUG-) (6)(7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

Phosphoproteome and gene expression profiling of ALK inhibition in neuroblastoma cell lines reveals conserved oncogenic pathways

et al. 2018

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Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor that is a clinical target of major interest in cancer. Mutations and rearrangements in ALK trigger the activation of the encoded receptor and its downstream signaling pathways. ALK mutations have been identified in both familial and sporadic neuroblastoma cases as well as in 30 to 40% of relapses, which makes ALK a bona fide target in neuroblastoma therapy. Tyrosine kinase inhibitors (TKIs) that target ALK are currently in clinical use for the treatment of patients with ALK-positive non–small cell lung cancer. However, monotherapy with the ALK inhibitor crizotinib has been less encouraging in neuroblastoma patients with ALK alterations, raising the question of whether combinatorial therapy would be more effective. In this study, we established both phosphoproteomic and gene expression profiles of ALK activity in neuroblastoma cells exposed to first- and third-generation ALK TKIs, to identify the underlying molecular mechanisms and identify relevant biomarkers, signaling networks, and new therapeutic targets. This analysis has unveiled various important leads for novel combinatorial treatment strategies for patients with neuroblastoma and an increased understanding of ALK signaling involved in this disease.

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