To 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.

Birmingham Children's Hospital NHS Foundation Trust UK

Centro Ricerca Tettamanti Clinica Pediatrica Università di Milano Bicocca Fondazione MBBM Ospedale San Gerardo Monza Italy

CLIP Department of Pediatric Hematology and Oncology 2 Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Department of Cancer Biology Institut Paoli Calmettes Marseille France

Department of Cytogenetics Leicester Royal Infirmary NHS Trust UK

Department of Haematology Our Lady's Children's Hospital Dublin Ireland

Department of Hematology Institut Paoli Calmettes Marseille France

Department of Hematology Leiden University Medical Center The Netherlands

Department of Laboratory Medicine Seoul St Mary's Hospital College of Medicine The Catholic University of Korea Seoul Republic of Korea

Department of Leukemia The University of Texas M D Anderson Cancer Center Houston TX USA

Department of Pathology St Jude Children's Research Hospital Memphis TN USA

Department of Pediatrics and the Center for Childhood Cancer Research Children's Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine PA USA

Department of Pediatrics Hematology Oncology Benioff Children's Hospital and the Helen Diller Family Comprehensive Cancer Center University of California San Francisco CA USA

Leukaemia Research Cytogenetics Group Northern Institute for Cancer Research Newcastle University Newcastle upon Tyne UK

Pediatric Hematology and Oncology Hannover Medical School Germany

South Australia Health and Medical Research Institute Adelaide Australia

St Anna Children's Hospital Childrens Cancer Research Institute Vienna Austria

University of New Mexico Cancer Center Albuquerque NM USA

Zobrazit více v PubMed

Golub TR, Goga A, Barker GF, et al. Oligomerization of the ABL tyrosine kinase by the Ets protein TEL in human leukemia. Mol Cell Biol. 1996;16(8):4107–4116. PubMed PMC

Hannemann JR, McManus DM, Kabarowski JH, Wiedemann LM. Haemopoietic transformation by the TEL/ABL oncogene. Br J Haematol. 1998;102(2):475–485. PubMed

Okuda K, Golub TR, Gilliland DG, Griffin JD. p210BCR/ABL, p190BCR/ABL, and TEL/ABL activate similar signal transduction pathways in hematopoietic cell lines. Oncogene. 1996;13(6):1147–1152. PubMed

Million RP, Aster J, Gilliland DG, Van Etten RA. The Tel-Abl (ETV6-Abl) tyrosine kinase, product of complex (9;12) translocations in human leukemia, induces distinct myeloproliferative disease in mice. Blood. 2002;99(12):4568–4577. PubMed

Den Boer ML, van Slegtenhorst M, De Menezes RX, et al. A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study. Lancet Oncol. 2009;10(2):125–134. PubMed PMC

Mullighan CG, Su X, Zhang J, et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med. 2009;360(5):470–480. PubMed PMC

Roberts KG, Li Y, Payne-Turner D, et al. Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. N Engl J Med. 2014;371(11):1005–1015. PubMed PMC

Roberts KG, Morin RD, Zhang J, et al. Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia. Cancer Cell. 2012;22(2):153–166. PubMed PMC

Carroll M, Ohno-Jones S, Tamura S, et al. CGP 57148, a tyrosine kinase inhibitor, inhibits the growth of cells expressing BCR-ABL, TEL-ABL, and TEL-PDGFR fusion proteins. Blood. 1997;90(12):4947–4952. PubMed

Okuda K, Weisberg E, Gilliland DG, Griffin JD. ARG tyrosine kinase activity is inhibited by STI571. Blood. 2001;97(8):2440–2448. PubMed

Harvey RC, Mullighan CG, Wang X, et al. Identification of novel cluster groups in pediatric high-risk B-precursor acute lymphoblastic leukemia with gene expression profiling: correlation with genome-wide DNA copy number alterations, clinical characteristics, and outcome. Blood. 2010;116(23):4874–4884. PubMed PMC

Lengline E, Beldjord K, Dombret H, Soulier J, Boissel N, Clappier E. Successful tyrosine kinase inhibitor therapy in a refractory B-cell precursor acute lymphoblastic leukemia with EBF1-PDGFRB fusion. Haematologica. 2013;98(11):e146–148. PubMed PMC

van der Veer A, Waanders E, Pieters R, et al. Independent prognostic value of BCR-ABL1-like signature and IKZF1 deletion, but not high CRLF2 expression, in children with B-cell precursor ALL. Blood. 2013;122(15):2622–2629. PubMed PMC

Weston BW, Hayden MA, Roberts KG, et al. Tyrosine kinase inhibitor therapy induces remission in a patient with refractory EBF1-PDGFRB-positive acute lymphoblastic leukemia. J Clin Oncol. 2013;31(25):e413–416. PubMed

Baeumler J, Szuhai K, Falkenburg JH, van Schie ML, Ottmann OG, Nijmeijer BA. Establishment and cytogenetic characterization of a human acute lymphoblastic leukemia cell line (ALL-VG) with ETV6/ABL1 rearrangement. Cancer Genet Cytogenet. 2008;185(1):37–42. PubMed

Malone A, Langabeer S, O’Marcaigh A, Storey L, Bacon CL, Smith OP. A doctor(s) dilemma: ETV6-ABL1 positive acute lymphoblastic leukaemia. Br J Haematol. 2010;151(1):101–102. PubMed

Mozziconacci MJ, Sainty D, Chabannon C. A fifteen-year cytogenetic remission following interferon treatment in a patient with an indolent ETV6-ABL positive myeloproliferative syndrome. Am J Hematol. 2007;82(7):688–689. PubMed

Park J, Kim M, Lim J, et al. Variant of ETV6/ABL1 gene is associated with leukemia phenotype. Acta Haematol. 2013;129(2):78–82. PubMed

Yeung DT, Moulton DJ, Heatley SL, et al. Relapse of BCR-ABL1-like ALL mediated by the ABL1 kinase domain mutation T315I following initial response to dasatinib treatment. Leukemia. 2015;29(1):230–232. PubMed

Zuna J, Zaliova M, Muzikova K, et al. Acute leukemias with ETV6/ABL1 (TEL/ABL) fusion: poor prognosis and prenatal origin. Genes Chromosomes Cancer. 2010;49(10):873–884. PubMed

Andreasson P, Johansson B, Carlsson M, et al. BCR/ABL-negative chronic myeloid leukemia with ETV6/ABL fusion. Genes Chromosomes Cancer. 1997;20(3):299–304. PubMed

Barbouti A, Ahlgren T, Johansson B, et al. Clinical and genetic studies of ETV6/ABL1-positive chronic myeloid leukaemia in blast crisis treated with imatinib mesylate. Br J Haematol. 2003;122(1):85–93. PubMed

Brunel V, Sainty D, Carbuccia N, et al. A TEL/ABL fusion gene on chromosome 12p13 in a case of Ph-, BCR- atypical CML. Leukemia. 1996;10:2003.

Gancheva K, Virchis A, Howard-Reeves J, et al. Myeloproliferative neoplasm with ETV6-ABL1 fusion: a case report and literature review. Mol Cytogenet. 2013;6(1):39. PubMed PMC

Kawamata N, Dashti A, Lu D, et al. Chronic phase of ETV6-ABL1 positive CML responds to imatinib. Genes Chromosomes Cancer. 2008;47(10):919–921. PubMed

Kelly JC, Shahbazi N, Scheerle J, et al. Insertion (12;9)(p13;q34q34): a cryptic rearrangement involving ABL1/ETV6 fusion in a patient with Philadelphia-negative chronic myeloid leukemia. Cancer Genet Cytogenet. 2009;192(1):36–39. PubMed

Keung YK, Beaty M, Steward W, Jackle B, Pettnati M. Chronic myelocytic leukemia with eosinophilia, t(9;12)(q34;p13), and ETV6-ABL gene rearrangement: case report and review of the literature. Cancer Genet Cytogenet. 2002;138(2):139–142. PubMed

La Starza R, Trubia M, Testoni N, et al. Clonal eosinophils are a morphologic hallmark of ETV6/ABL1 positive acute myeloid leukemia. Haematologica. 2002;87(8):789–794. PubMed

Lin H, Guo JQ, Andreeff M, Arlinghaus RB. Detection of dual TEL-ABL transcripts and a Tel-Abl protein containing phosphotyrosine in a chronic myeloid leukemia patient. Leukemia. 2002;16(2):294–297. PubMed

Meyer-Monard S, Muhlematter D, Streit A, et al. Broad molecular screening of an unclassifiable myeloproliferative disorder reveals an unexpected ETV6/ABL1 fusion transcript. Leukemia. 2005;19(6):1096–1099. PubMed

Nand R, Bryke C, Kroft SH, Divgi A, Bredeson C, Atallah E. Myeloproliferative disorder with eosinophilia and ETV6-ABL gene rearrangement: efficacy of second-generation tyrosine kinase inhibitors. Leuk Res. 2009;33(8):1144–1146. PubMed

O’Brien SG, Vieira SA, Connors S, et al. Transient response to imatinib mesylate (STI571) in a patient with the ETV6-ABL t(9;12) translocation. Blood. 2002;99(9): 3465–3467. PubMed

Papadopoulos P, Ridge SA, Boucher CA, Stocking C, Wiedemann LM. The novel activation of ABL by fusion to an ets-related gene, TEL. Cancer Res. 1995;55(1):34–38. PubMed

Perna F, Abdel-Wahab O, Levine RL, Jhanwar SC, Imada K, Nimer SD. ETV6-ABL1-positive “chronic myeloid leukemia”: clinical and molecular response to tyrosine kinase inhibition. Haematologica. 2011;96(2):342–343. PubMed PMC

Song JS, Shin SY, Lee ST, Kim HJ, Kim SH. A cryptic ETV6/ABL1 rearrangement represents a unique fluorescence in situ hybridization signal pattern in a patient with B acute lymphoblastic leukemia. Ann Lab Med. 2014;34(6):475–477. PubMed PMC

Tirado CA, Sebastian S, Moore JO, Gong JZ, Goodman BK. Molecular and cytogenetic characterization of a novel rearrangement involving chromosomes 9, 12, and 17 resulting in ETV6 (TEL) and ABL fusion. Cancer Genet Cytogenet. 2005;157(1):74–77. PubMed

Van Limbergen H, Beverloo HB, van Drunen E, et al. Molecular cytogenetic and clinical findings in ETV6/ABL1-positive leukemia. Genes Chromosomes Cancer. 2001;30(3): 274–282. PubMed

Yamamoto K, Yakushijin K, Nakamachi Y, et al. 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). Ann Hematol. 2014;93(8): 1435–1438. PubMed

Zhou MH, Gao L, Jing Y, et al. Detection of ETV6 gene rearrangements in adult acute lymphoblastic leukemia. Ann Hematol. 2012;91(8):1235–1243. PubMed

Hehlmann R, Heimpel H, Hasford J, et al. Randomized comparison of interferon-alpha with busulfan and hydroxyurea in chronic myelogenous leukemia. The German CML Study Group. Blood. 1994;84(12):4064–4077. PubMed

Choi HJ, Kim HR, Shin MG, et al. Spectra of chromosomal aberrations in 325 leukemia patients and implications for the development of new molecular detection systems. J Korean Med Sci. 2011;26(7):886–892. PubMed PMC

Janssen JW, Ridge SA, Papadopoulos P, et al. The fusion of TEL and ABL in human acute lymphoblastic leukaemia is a rare event. Br J Haematol. 1995;90(1):222–224. PubMed

Miller DR, Coccia PF, Bleyer WA, et al. Early response to induction therapy as a predictor of disease-free survival and late recurrence of childhood acute lymphoblastic leukemia: a report from the Childrens Cancer Study Group. J Clin Oncol. 1989;7(12):1807–1815. PubMed

Moricke A, Zimmermann M, Reiter A, et al. Long-term results of five consecutive trials in childhood acute lymphoblastic leukemia performed by the ALL-BFM study group from 1981 to 2000. Leukemia. 2010;24(2): 265–284. PubMed

van Dongen JJ, Seriu T, Panzer-Grumayer ER, et al. Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood. Lancet. 1998;352(9142):1731–1738. PubMed

Pane F, Intrieri M, Quintarelli C, Izzo B, Muccioli GC, Salvatore F. BCR/ABL genes and leukemic phenotype: from molecular mechanisms to clinical correlations. Oncogene. 2002;21(56):8652–8667. PubMed

Million RP, Harakawa N, Roumiantsev S, Varticovski L, Van Etten RA. A direct binding site for Grb2 contributes to transformation and leukemogenesis by the Tel-Abl (ETV6-Abl) tyrosine kinase. Mol Cell Biol. 2004;24(11):4685–4695. PubMed PMC

Million RP, Van Etten RA. The Grb2 binding site is required for the induction of chronic myeloid leukemia-like disease in mice by the Bcr/Abl tyrosine kinase. Blood. 2000;96(2):664–670. PubMed

Moorman AV, Enshaei A, Schwab C, et al. A novel integrated cytogenetic and genomic classification refines risk stratification in pediatric acute lymphoblastic leukemia. Blood. 2014;124(9):1434–1444. PubMed

Mullighan CG, Goorha S, Radtke I, et al. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature. 2007;446(7137):758–764. PubMed

Mullighan CG, Miller CB, Radtke I, et al. BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature. 2008;453(7191):110–114. PubMed

Virely C, Moulin S, Cobaleda C, et al. Haploinsufficiency of the IKZF1 (IKAROS) tumor suppressor gene cooperates with BCR-ABL in a transgenic model of acute lymphoblastic leukemia. Leukemia. 2010;24(6):1200–1204. PubMed

Williams RT, Roussel MF, Sherr CJ. Arf gene loss enhances oncogenicity and limits imatinib response in mouse models of Bcr-Abl-induced acute lymphoblastic leukemia. Proc Natl Acad Sci USA. 2006;103(17):6688–6693. PubMed PMC

Ghazavi F, Clappier E, Lammens T, et al. CD200/BTLA deletions in pediatric precursor B-cell acute lymphoblastic leukemia treated according to the EORTC-CLG 58951 protocol. Haematologica. 2015;100(10): 1311–1319. PubMed PMC

Iacobucci I, Ferrari A, Lonetti A, et al. CDKN2A/B alterations impair prognosis in adult BCR-ABL1-positive acute lymphoblastic leukemia patients. Clin Cancer Res. 2011;17(23):7413–7423. PubMed

Olsson L, Castor A, Behrendtz M, et al. Deletions of IKZF1 and SPRED1 are associated with poor prognosis in a population-based series of pediatric B-cell precursor acute lymphoblastic leukemia diagnosed between 1992 and 2011. Leukemia. 2014;28(2):302–310. PubMed

van der Veer A, Zaliova M, Mottadelli F, et al. IKZF1 status as a prognostic feature in BCR-ABL1-positive childhood ALL. Blood. 2014;123(11):1691–1698. PubMed

Roberts KG, Pei D, Campana D, et al. Outcomes of children with BCR-ABL1-like acute lymphoblastic leukemia treated with risk-directed therapy based on the levels of minimal residual disease. J Clin Oncol. 2014;32(27):3012–3020. PubMed PMC

Fielding AK, Rowe JM, Buck G, et al. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014;123(6):843–850. PubMed PMC

The Clinical Utility of Optical Genome Mapping for the Assessment of Genomic Aberrations in Acute Lymphoblastic Leukemia

Genomic landscape of pediatric B-other acute lymphoblastic leukemia in a consecutive European cohort

New biological and genetic classification and therapeutically relevant categories in childhood B-cell precursor acute lymphoblastic leukemia

An activating mutation of GNB1 is associated with resistance to tyrosine kinase inhibitors in ETV6-ABL1-positive leukemia