Transient response to imatinib mesylate (STI571) in a patient with the ETV6-ABL t(9;12) translocation

O’Brien, Stephen G.; Vieira, Sônia; Connors, Samantha; Bown, Nick; Chang, James; Capdeville, Renaud; Melo, Junia V.

doi:10.1182/blood.v99.9.3465

Cited by 48 publications

(48 citation statements)

References 13 publications

(11 reference statements)

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“…11 ABL is also activated by fusion to nucleoporin 214 (NUP214) in 5 percent of T-cell acute lymphoblastic leukemias 15 and to ETV6 (also known as TEL) in rare cases of atypical CML and acute leukemia, 13 both potential targets for imatinib. 14 Imatinib should also have activity in cancers caused by activated PDGFRs and c-KIT. PDGFR a is activated by cryptic interstitial chromosome 4 deletions that generate a FIP1L1-PDGFR a fusion TK in some patients with hypereosinophilic tks as targets in the treatment of malignant hematologic disorders , which induces oligomerization of the receptor and intermolecular phosphorylation (P, in yellow) of the activation-loop tyrosine.…”

Section: Strategies To Target Tk S In Cancer Therapymentioning

confidence: 99%

Tyrosine Kinases as Targets for Cancer Therapy

Krause

Etten²

2005

N Engl J Med

1,219

821

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Section: Strategies To Target Tk S In Cancer Therapymentioning

confidence: 99%

Tyrosine Kinases as Targets for Cancer Therapy

Krause

Etten²

2005

N Engl J Med

1,219

821

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“…1,18,[21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] Standard diagnostics, including molecular genetics, karyotyping and fluorescence in-situ hybridization (FISH) were performed according to the standard practice of the local diagnostic laboratories. Basic clinical/outcome data were collected from treating centers.…”

Section: Patientsmentioning

confidence: 99%

Characterization of leukemias with ETV6-ABL1 fusion

et al. 2016

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T o characterize the incidence, clinical features and genetics of ETV6-ABL1 leukemias, representing targetable kinase-activating lesions, we analyzed 44 new and published cases of ETV6-ABL1-positive hematologic malignancies [22 cases of acute lymphoblastic leukemia (13 children, 9 adults) and 22 myeloid malignancies (18 myeloproliferative neoplasms, 4 acute myeloid leukemias)]. The presence of the ETV6-ABL1 fusion was ascertained by cytogenetics, fluorescence in-situ hybridization, reverse transcriptase-polymerase chain reaction and RNA sequencing. Genomic and gene expression profiling was performed by single nucleotide polymorphism and expression arrays. Systematic screening of more than 4,500 cases revealed that in acute lymphoblastic leukemia ETV6-ABL1 is rare in childhood (0.17% cases) and slightly more common in adults (0.38%). There is no systematic screening of myeloproliferative neoplasms; however, the number of ETV6-ABL1-positive cases and the relative incidence of acute lymphoblastic leukemia and myeloproliferative neoplasms suggest that in adulthood ETV6-ABL1 is more common in BCR-ABL1-negative chronic myeloid leukemia-like myeloproliferations than in acute lymphoblastic leukemia. The genomic profile of ETV6-ABL1 acute lymphoblastic leukemia resembled that of BCR-ABL1 and BCR-ABL1-like cases with 80% of patients having concurrent CDKN2A/B and IKZF1 deletions. In the gene expression profiling all the ETV6-ABL1-positive samples clustered in close vicinity to BCR-ABL1 cases. All but one of the cases of ETV6-ABL1 acute lymphoblastic leukemia were classified as BCR-ABL1-like by a standardized assay. Over 60% of patients died, irrespectively of the disease or age subgroup examined. In conclusion, ETV6-ABL1 fusion occurs in both lymphoid and myeloid leukemias; the genomic profile and clinical behavior resemble BCR-ABL1-positive malignancies, including the unfavorable prognosis, particularly of acute leukemias. The poor outcome suggests that treatment with tyrosine kinase inhibitors should be considered for patients with this fusion.

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“…The association of Tel-Abl ⌬e5 with a patient with B-ALL is more difficult to explain, but there was no karyotype reported for this patient and it is possible that the Tel-Abl fusion was not the principal cause of this leukemia. It would have been interesting to see if this patient would have responded clinically to the Abl kinase inhibitor imatinib (40), which has also been shown to inhibit Tel-Abl (4). Further comparative studies of Tel-Ablexpressing human and murine B-lymphoid leukemias will be necessary to determine the pathogenic role of Grb2 binding in human B-ALL.…”

Section: Discussionmentioning

confidence: 99%

“…Fusion of the ABL gene to a different partner, the TEL (ETV6) gene on chromosome 12p13, has been reported to occur in a small number of patients with leukemia, some who had acute leukemia of B-lymphoid (43), T-lymphoid (60), or myeloid (13,40) origin and some who presented with atypical (3,28) or typical (1,60) CML. TEL encodes a ubiquitously expressed 452-amino-acid protein with homology to the Ets family of transcription factors (12).…”

mentioning

confidence: 99%

A Direct Binding Site for Grb2 Contributes to Transformation and Leukemogenesis by the Tel-Abl (ETV6-Abl) Tyrosine Kinase

Million

Harakawa

Rumyantsev

et al. 2004

Molecular and Cellular Biology

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A direct binding site for the Grb2 adapter protein is required for the induction of fatal chronic myeloid leukemia (CML)-like disease in mice by Bcr-Abl. Here, we demonstrate direct binding of Grb2 to the Tel-Abl (ETV6-Abl) fusion protein, the product of complex (9;12) chromosomal translocations in human leukemia, via tyrosine 314 encoded by TEL exon 5. A Tel-Abl point mutant (Y314F) and a splice variant without TEL exon 5 sequences (⌬e5) lacked Grb2 interaction and exhibited decreased binding and phosphorylation of the scaffolding protein Gab2 and impaired activation of phosphatidylinositol 3-kinase, Akt, and extracellular signal-regulated kinase/mitogen-activated protein kinase in hematopoietic cells. Tel-Abl Y314F and ⌬e5 were unable to transform fibroblasts to anchorage-independent growth and were defective for B-lymphoid transformation in vitro and lymphoid leukemogenesis in vivo. Previously, we demonstrated that full-length Tel-Abl induced two distinct myeloproliferative diseases in mice: CML-like leukemia similar to that induced by Bcr-Abl and a novel syndrome of small-bowel myeloid infiltration endotoxemia and hepatic and renal failure. Lack of the Grb2 binding site had no effect on development of small bowel syndrome but significantly attenuated the induction of CML-like disease by Tel-Abl. These results suggest that direct binding of Grb2 is a common mechanism contributing to leukemogenesis by oncogenic Abl fusion proteins.The BCR-ABL oncogene, the product of the t(9;22) Philadelphia (Ph) chromosome translocation, encodes a dysregulated cytoplasmic protein-tyrosine kinase, Bcr-Abl, that is the direct cause of the myeloproliferative disease chronic myeloid leukemia (CML) and Ph ϩ acute B-lymphoblastic leukemia (B-ALL). Bcr-Abl activates multiple intracellular signaling pathways including Ras, mitogen-activated protein kinase (MAPK), Jun N-terminal kinase (JNK), STAT5, and phosphatidylinositol 3-kinase (PI 3-kinase) (52) and transforms fibroblasts (33), cytokine-dependent hematopoietic cell lines (6,18), and primary bone marrow B-lymphoid cells (36) in vitro. Retroviral transduction of the BCR-ABL gene into murine bone marrow followed by transplantation into irradiated recipient mice results in the development of either CML-like myeloproliferative disease (30,44,62) or B-ALL (50) in all recipients, depending on the transduction conditions. The mouse retroviral bone marrow transduction/transplantation system provides accurate and quantitative models of human CML and Ph ϩ B-ALL (58) that have proven useful for analyzing the molecular pathophysiology of these diseases (15,29,30,39,50,63).Fusion of the ABL gene to a different partner, the TEL (ETV6) gene on chromosome 12p13, has been reported to occur in a small number of patients with leukemia, some who had acute leukemia of B-lymphoid (43), T-lymphoid (60), or myeloid (13, 40) origin and some who presented with atypical (3, 28) or typical (1, 60) CML. TEL encodes a ubiquitously expressed 452-amino-acid protein with homology to the Ets family of transcripti...

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Transient response to imatinib mesylate (STI571) in a patient with the ETV6-ABL t(9;12) translocation

Cited by 48 publications

References 13 publications

Tyrosine Kinases as Targets for Cancer Therapy

Tyrosine Kinases as Targets for Cancer Therapy

Characterization of leukemias with ETV6-ABL1 fusion

A Direct Binding Site for Grb2 Contributes to Transformation and Leukemogenesis by the Tel-Abl (ETV6-Abl) Tyrosine Kinase

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