Characterization of leukemias with ETV6-ABL1 fusion

Marketa Zaliova, Anthony Moorman, Giovanni Cazzaniga, Martin Stanulla, Richard C. Harvey, Kathryn G. Roberts, Sue L. Heatley, Mignon L. Loh, Marina Konopleva, I. Ming Chen, Olga Zimmermannova, Claire Schwab, Owen Smith, Marie Joelle Mozziconacci, Christian Chabannon, Myungshin Kim, J. H. Frederik Falkenburg, Alice Norton, Karen Marshall, Oskar A. HaasJulia Starkova, Jan Stuchly, Stephen P. Hunger, Deborah White, Charles G. Mullighan, Cheryl L. Willman, Jan Stary, Jan Trka, Jan Zuna

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1082-1093
Number of pages12
JournalHaematologica
Volume101
Issue number9
DOIs
StatePublished - Jan 1 2016
Externally publishedYes

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Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia
Gene Expression Profiling
Neoplasms
RNA Sequence Analysis
Lymphoid Leukemia
Myeloid Leukemia
Incidence
Hematologic Neoplasms
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Reverse Transcriptase Polymerase Chain Reaction
Fluorescence In Situ Hybridization
Acute Myeloid Leukemia
Cytogenetics
Protein-Tyrosine Kinases
Single Nucleotide Polymorphism
Phosphotransferases

ASJC Scopus subject areas

  • Hematology

Cite this

Zaliova, M., Moorman, A., Cazzaniga, G., Stanulla, M., Harvey, R. C., Roberts, K. G., ... Zuna, J. (2016). Characterization of leukemias with ETV6-ABL1 fusion. Haematologica, 101(9), 1082-1093. https://doi.org/10.3324/haematol.2016.144345

Characterization of leukemias with ETV6-ABL1 fusion. / Zaliova, Marketa; Moorman, Anthony; Cazzaniga, Giovanni; Stanulla, Martin; Harvey, Richard C.; Roberts, Kathryn G.; Heatley, Sue L.; Loh, Mignon L.; Konopleva, Marina; Chen, I. Ming; Zimmermannova, Olga; Schwab, Claire; Smith, Owen; Mozziconacci, Marie Joelle; Chabannon, Christian; Kim, Myungshin; Frederik Falkenburg, J. H.; Norton, Alice; Marshall, Karen; Haas, Oskar A.; Starkova, Julia; Stuchly, Jan; Hunger, Stephen P.; White, Deborah; Mullighan, Charles G.; Willman, Cheryl L.; Stary, Jan; Trka, Jan; Zuna, Jan.

In: Haematologica, Vol. 101, No. 9, 01.01.2016, p. 1082-1093.

Research output: Contribution to journalArticle

Zaliova, M, Moorman, A, Cazzaniga, G, Stanulla, M, Harvey, RC, Roberts, KG, Heatley, SL, Loh, ML, Konopleva, M, Chen, IM, Zimmermannova, O, Schwab, C, Smith, O, Mozziconacci, MJ, Chabannon, C, Kim, M, Frederik Falkenburg, JH, Norton, A, Marshall, K, Haas, OA, Starkova, J, Stuchly, J, Hunger, SP, White, D, Mullighan, CG, Willman, CL, Stary, J, Trka, J & Zuna, J 2016, 'Characterization of leukemias with ETV6-ABL1 fusion', Haematologica, vol. 101, no. 9, pp. 1082-1093. https://doi.org/10.3324/haematol.2016.144345
Zaliova M, Moorman A, Cazzaniga G, Stanulla M, Harvey RC, Roberts KG et al. Characterization of leukemias with ETV6-ABL1 fusion. Haematologica. 2016 Jan 1;101(9):1082-1093. https://doi.org/10.3324/haematol.2016.144345
Zaliova, Marketa ; Moorman, Anthony ; Cazzaniga, Giovanni ; Stanulla, Martin ; Harvey, Richard C. ; Roberts, Kathryn G. ; Heatley, Sue L. ; Loh, Mignon L. ; Konopleva, Marina ; Chen, I. Ming ; Zimmermannova, Olga ; Schwab, Claire ; Smith, Owen ; Mozziconacci, Marie Joelle ; Chabannon, Christian ; Kim, Myungshin ; Frederik Falkenburg, J. H. ; Norton, Alice ; Marshall, Karen ; Haas, Oskar A. ; Starkova, Julia ; Stuchly, Jan ; Hunger, Stephen P. ; White, Deborah ; Mullighan, Charles G. ; Willman, Cheryl L. ; Stary, Jan ; Trka, Jan ; Zuna, Jan. / Characterization of leukemias with ETV6-ABL1 fusion. In: Haematologica. 2016 ; Vol. 101, No. 9. pp. 1082-1093.
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abstract = "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.",
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T1 - Characterization of leukemias with ETV6-ABL1 fusion

AU - Zaliova, Marketa

AU - Moorman, Anthony

AU - Cazzaniga, Giovanni

AU - Stanulla, Martin

AU - Harvey, Richard C.

AU - Roberts, Kathryn G.

AU - Heatley, Sue L.

AU - Loh, Mignon L.

AU - Konopleva, Marina

AU - Chen, I. Ming

AU - Zimmermannova, Olga

AU - Schwab, Claire

AU - Smith, Owen

AU - Mozziconacci, Marie Joelle

AU - Chabannon, Christian

AU - Kim, Myungshin

AU - Frederik Falkenburg, J. H.

AU - Norton, Alice

AU - Marshall, Karen

AU - Haas, Oskar A.

AU - Starkova, Julia

AU - Stuchly, Jan

AU - Hunger, Stephen P.

AU - White, Deborah

AU - Mullighan, Charles G.

AU - Willman, Cheryl L.

AU - Stary, Jan

AU - Trka, Jan

AU - Zuna, Jan

PY - 2016/1/1

Y1 - 2016/1/1

N2 - 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.

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