Extramedullary T-lymphoid blast crisis of an ETV6/ABL1-positive myeloproliferative neoplasm with t(9;12)(q34;p13) and t(7;14)(p13;q11.2)

Yamamoto, Katsuya; Yakushijin, Kimikazu; Nakamachi, Yuji; Miyata, Yoshiharu; Yukitoshi, Sanada; Tanaka, Yasuhiro; Okamura, Atsuo; Hayashi, Yoshitake; Matsuoka, Hiroshi; Minami, Hironobu

doi:10.1007/s00277-013-1975-y

Cited by 13 publications

(12 citation statements)

References 10 publications

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“…The cohort consisted of 44 patients with an ETV6-ABL1 fusion and comprised newly identified cases (n=9), published cases with additional new data (n=11) 7,8,[15][16][17][18][19][20] and cases with re-examined published data (n=24). 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

Žaliová

Moorman

Cazzaniga

et al. 2015

Blood

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Introduction The ETV6-ABL1 (TEL-ABL) fusion gene is a rare but recurrent genetic aberration found in various hematological malignancies in children and adults. Due to the inverse orientation of ETV6 (12p13) and ABL1 (9q34) an in-frame fusion cannot be produced by a simple balanced translocation and thus results from a complex rearrangement. Alternative splicing generates two fusion transcripts - type A and B without and with ETV6 exon 5, respectively. Both transcripts encode a constitutively active chimeric tyrosine kinase. The effect of ETV6-ABL1 on cellular proliferation, cell survival and transforming capacity mirrors that seen in BCR-ABL1-positive cases. There is a renewed interest in ETV6-ABL1 since the discovery of a "BCR-ABL1-like" (or "Ph-like") gene expression profile (GEP) among B-cell precursor (BCP) ALL cases lacking an established chromosomal abnormality (so-called "B-other ALL"). The BCR-ABL1-like GEP resembles the BCR-ABL1 GEP because both are driven by the activation of kinase signaling. In vitro studies suggest that many of these kinase fusions, including ETV6-ABL1, are sensitive to specific tyrosine kinase inhibitors (TKI), thus representing a promising and relevant therapeutic target, especially given the reported unfavorable prognosis of BCR-ABL1-like ALL. The aim of this study was to characterize the incidence, clinical features and genetic profile of ETV6-ABL1 leukemias with a focus on ALL as an example of a targetable kinase-activating lesion. Patients and methods The cohort totals 44 ETV6-ABL1 patients and comprises newly identified cases (n=9), published cases with additional new data (n=11) and cases with re-examined published data (n=24). Half of the patients (n=22) was diagnosed with ALL (13 children, 9 adults) while 22 had a myeloid malignancy (18 CML-like myeloproliferative neoplasm (MPN), 4 AML). Besides routine diagnostic examinations, we analyzed the presence of fusion transcript variants, genomic profile using MLPA and SNP-array, gene expression profile on microarrays and the presence of BCR-ABL1-like expression signature using quantitative PCR-based low density expression arrays. Results Systematic screening of >3500 cases revealed that ETV6-ABL1 is rare in childhood ALL (0.17% cases) and slightly more prevalent in adult ALL (0.38%). The equal number of MPN and ALL cases and the relative incidence of ALL and MPN in adulthood suggests ETV6-ABL1 is more common in MPN. The type B variant (including ETV6 exon 5) is the dominant transcript and its detection by PCR screening is a more reliable diagnostic approach than FISH with commercial probes for ETV6-RUNX1 and BCR-ABL1. In BCP ALL, ETV6-ABL1 fusion always localized to the der(12) whereas in T-ALL and myeloid cases the fusion localized to the der(9), der(12) or a third chromosome. The genomic profile of ETV6-ABL1 ALL resembled BCR-ABL1 and BCR-ABL1-like ALL with 80% cases having concurrent CDKN2A/B and IKZF1 deletions. The gene expression signature of ETV6-ABL1 ALL cases was more similar to BCR-ABL1 than BCR-ABL1-like principally due to low CRLF2 expression. Nonetheless, 11/12 ETV6-ABL1 ALL cases were classified as BCR-ABL1-like by a standardized qPCR-based expression array. Survival of ETV6-ABL1-positive ALL is 46% in children (6/13 alive) and 13% in adults (1/8 alive). While prognosis of childhood ALL patients responding well to initial treatment seems to be favorable (3/3 with end-induction MRD < 5x10e-5 are in the 1st remission >4 years from diagnosis), children with inferior response have very poor prognosis. Survival of MPN is 50% (9/18 alive) and depends on the disease status at diagnosis (chronic vs. blastic phase). Conclusion ETV6-ABL1 fusion occurs in lymphoid and myeloid leukemia. Its genomic and expression profile, spectrum of malignancies and clinical behavior resemble BCR-ABL1, including the unfavorable prognosis, particularly in acute leukemias. Systematic screening confirmed low frequency of ETV6-ABL1 fusion in ALL. Due to high false-negative rate of FISH, PCR diagnostics are recommended for systematic screening of ALL and FISH-negative CML-like MPN. Despite the generally poor outcome, childhood ALL cases with favorable early treatment response can be treated with standard modern therapeutic protocols. To improve prognosis of the others, early diagnostics of ETV6-ABL1 and treatment with TKI should be considered. Supported by grants IGA MZ NT/13170-4 and GAUK 694414. Disclosures Mullighan: Amgen: Honoraria; Incyte: Consultancy.

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Section: Patientsmentioning

confidence: 99%

Characterization of Leukemias with ETV6-ABL1 Fusion

Žaliová

Moorman

Cazzaniga

et al. 2015

Blood

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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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“…After a median of 2 years, durable complete remissions were only observed on nilotinib, dasatinib or after allo SCT. We identified an additional 14 cases in the literature [16–27,53,54] with adequate data on response on TKI and follow‐up. In concordance with our findings, imatinib can induce but not maintain long‐term remissions 25 .…”

Section: Discussionmentioning

confidence: 99%

“…Beside ALL, the phenotype may resemble in adults a myeloid neoplasm such as atypical chronic myeloid leukemia (aCML), chronic eosinophilic leukemia (CEL), myelodysplastic/myeloproliferative neoplasm unclassified (MDS/MPN‐U) or MPN‐U which are diagnosed in CP or BP. However, data on treatment and response to ABL1 inhibitors such as imatinib, nilotinib or dasatinib are limited to case reports or small cases series 16‐27 …”

Section: Introductionmentioning

confidence: 99%

“…We therefore sought to evaluate the clinical characteristics and response to various TKI in 18 patients with myeloid neoplasms and associated PCM1‐JAK2 , BCR‐JAK2 or ETV6‐ABL1 fusion genes. In an extended analysis, we integrated our data into the reports of 40 patients with JAK2 fusion genes ( PCM1‐JAK2 , n = 28) 8,9,12‐15,28‐40 or BCR‐JAK2 (n = 12) 41‐52 and 14 patients with TKI‐treated ETV6‐ABL1 positive chronic myeloid neoplasms 16‐27,53,54 . This analysis provides a comprehensive overview of responses to TKIs in patients with these rare fusions.…”

Section: Introductionmentioning

confidence: 99%

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Response to tyrosine kinase inhibitors in myeloid neoplasms associated with PCM1‐JAK2, BCR‐JAK2 and ETV6‐ABL1 fusion genes

et al. 2020

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We report on 18 patients with myeloid neoplasms and associated tyrosine kinase (TK) fusion genes on treatment with the TK inhibitors (TKI) ruxolitinib (PCM1‐JAK2, n = 8; BCR‐JAK2, n = 1) and imatinib, nilotinib or dasatinib (ETV6‐ABL1, n = 9). On ruxolitinib (median 24 months, range 2‐36 months), a complete hematologic response (CHR) and complete cytogenetic response (CCR) was achieved by five of nine and two of nine patients, respectively. However, ruxolitinib was stopped in eight of nine patients because of primary resistance (n = 3), progression (n = 3) or planned allogeneic stem cell transplantation (allo SCT, n = 2). At a median of 36 months (range 4‐78 months) from diagnosis, five of nine patients are alive: four of six patients after allo SCT and one patient who remains on ruxolitinib. In ETV6‐ABL1 positive patients, a durable CHR was achieved by four of nine patients (imatinib with one of five, nilotinib with two of three, dasatinib with one of one). Because of inadequate efficacy (lack of hematological and/or cytogenetic/molecular response), six of nine patients (imatinib, n = 5; nilotinib, n = 1) were switched to nilotinib or dasatinib. At a median of 23 months (range 3‐60 months) from diagnosis, five of nine patients are in CCR or complete molecular response (nilotinib, n = 2; dasatinib, n = 2; allo SCT, n = 1) while two of nine patients have died. We conclude that (a) responses on ruxolitinib may only be transient in the majority of JAK2 fusion gene positive patients with allo SCT being an important early treatment option, and (b) nilotinib or dasatinib may be more effective than imatinib to induce durable complete remissions in ETV6‐ABL1 positive patients.

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Extramedullary T-lymphoid blast crisis of an ETV6/ABL1-positive myeloproliferative neoplasm with t(9;12)(q34;p13) and t(7;14)(p13;q11.2)

Cited by 13 publications

References 10 publications

Characterization of Leukemias with ETV6-ABL1 Fusion

Characterization of Leukemias with ETV6-ABL1 Fusion

Characterization of leukemias with ETV6-ABL1 fusion

Response to tyrosine kinase inhibitors in myeloid neoplasms associated with PCM1‐JAK2, BCR‐JAK2 and ETV6‐ABL1 fusion genes

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