Molecular characterization and clinical outcome of B-cell precursor acute lymphoblastic leukemia with IG-MYC rearrangement

Simon Bomken; Amir Enshaei; Edward C. Schwalbe; Aneta Mikulasova; Yunfeng Dai; Masood Zaka; Kent T.M. Fung; Matthew Bashton; Huezin Lim; Lisa Jones; Nefeli Karataraki; Emily Winterman; Cody Ashby; Andishe Attarbaschi; Yves Bertrand; Jutta Bradtke; Barbara Buldini; G. A.Amos Burke; Giovanni Cazzaniga; Gudrun Göhring; Hesta A. de Groot-Kruseman; Claudia Haferlach; Luca Lo Nigro; Mayur Parihar; Adriana Plesa; Emma Seaford; Edwin Sonneveld; Sabine Strehl; Vincent H.J. van der Velden; Vikki Rand; Stephen P. Hunger; Christine J. Harrison; Chris M. Bacon; Frederik W. van Delft; Mignon L. Loh; John Moppett; Josef Vormoor; Brian A. Walker; Anthony V. Moorman; Lisa J. Russell

doi:10.3324/haematol.2021.280557

Molecular characterization and clinical outcome of B-cell precursor acute lymphoblastic leukemia with IG-MYC rearrangement

Simon Bomken^*, Amir Enshaei, Edward C. Schwalbe, Aneta Mikulasova, Yunfeng Dai, Masood Zaka, Kent T.M. Fung, Matthew Bashton, Huezin Lim, Lisa Jones, Nefeli Karataraki, Emily Winterman, Cody Ashby, Andishe Attarbaschi, Yves Bertrand, Jutta Bradtke, Barbara Buldini, G. A.Amos Burke, Giovanni Cazzaniga, Gudrun GöhringHesta A. de Groot-Kruseman, Claudia Haferlach, Luca Lo Nigro, Mayur Parihar, Adriana Plesa, Emma Seaford, Edwin Sonneveld, Sabine Strehl, Vincent H.J. van der Velden, Vikki Rand, Stephen P. Hunger, Christine J. Harrison, Chris M. Bacon, Frederik W. van Delft, Mignon L. Loh, John Moppett, Josef Vormoor, Brian A. Walker, Anthony V. Moorman, Lisa J. Russell^*

^*Corresponding author for this work

Cancer and Genomic Sciences

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Abstract

Rarely, immunophenotypically immature B-cell precursor acute lymphoblastic leukemia (BCP-ALL) carries an immunoglobulin-MYC rearrangement (IG-MYC-r). This can result in diagnostic confusion with Burkitt lymphoma/leukemia and use of individualized treatment schedules of unproven efficacy. Here we compare the molecular characteristics of these conditions and investigate historic clinical outcome data. We identified 90 cases registered in a national BCP-ALL clinical trial/registry. When present, diagnostic material underwent cytogenetic, exome, methylome and transcriptome analyses. The outcomes analyzed were 3-year event-free survival and overall survival. IG-MYC-r was identified in diverse cytogenetic backgrounds, co-existing with either established BCP-ALL-specific abnormalities (high hyperdiploidy, n=3; KMT2A-rearrangement, n=6; iAMP21, n=1; BCR-ABL1, n=1); BCL2/BCL6-rearrangements (n=15); or, most commonly, as the only defining feature (n=64). Within this final group, precursor-like V(D)J breakpoints predominated (8/9) and KRAS mutations were common (5/11). DNA methylation identified a cluster of V(D)J-rearranged cases, clearly distinct from Burkitt leukemia/lymphoma. Children with IG-MYC-r within that subgroup had a 3-year event-free survival of 47% and overall survival of 60%, representing a high-risk BCP-ALL. To develop effective management strategies this group of patients must be allowed access to contemporary, minimal residual disease-adapted, prospective clinical trial protocols.

Original language	English
Pages (from-to)	717-731
Number of pages	15
Journal	Haematologica
Volume	108
Issue number	3
Early online date	28 Apr 2022
DOIs	https://doi.org/10.3324/haematol.2021.280557
Publication status	Published - Mar 2023

Bibliographical note

Funding Information:
We would like to thank those who provided financial support. Kay Kendall Leukaemia Fund (KKL515), Wellcome Trust Institutional Strategic Support Fund (204787/Z/16/Z), The Newcastle upon Tyne Hospitals NHS charity and KidsCan Children’s Cancer Research and The Little Princess Trust (to LJR). LJR held a Newcastle University Research Fellowship and A.M. a Newcastle University Faculty Fellowship. SB was supported by The Sir Bobby Robson Foundation and an MRC Clinician Scientist Fellowship MR/S021590/1. COG funding was available through U10 CA98413 and U10 CA180899 (COG Statistics and Data Center grants), U24 CA114766 and U24-CA196173 (COG Specimen Banking). AVM and CJH were supported by Blood Cancer UK (15036) and Cancer Research UK (A21019, Moorman and Fielding). LLN was partially supported by MFAG 2009 – AIRC (Italian Association for Cancer Research) (Lo Nigro). VR was supported by a Bloodwise (formerly Leukaemia and Lymphoma Research) Senior Bennett Fellowship (#12005), the JGW Patterson Foundation and the Little Princess Trust. MZ was supported by North East Promenaders. GC was supported by the Italian Association for Cancer Research (Grant n.IG17593) and Comitato Maria Letizia Verga.

Publisher Copyright:
©2023 Ferrata Storti Foundation.

ASJC Scopus subject areas

Hematology

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Bomken, S., Enshaei, A., Schwalbe, E. C., Mikulasova, A., Dai, Y., Zaka, M., Fung, K. T. M., Bashton, M., Lim, H., Jones, L., Karataraki, N., Winterman, E., Ashby, C., Attarbaschi, A., Bertrand, Y., Bradtke, J., Buldini, B., Burke, G. A. A., Cazzaniga, G., ... Russell, L. J. (2023). Molecular characterization and clinical outcome of B-cell precursor acute lymphoblastic leukemia with IG-MYC rearrangement. Haematologica, 108(3), 717-731. https://doi.org/10.3324/haematol.2021.280557

@article{60035e87338b4b9e91ebe57f688f54bd,

title = "Molecular characterization and clinical outcome of B-cell precursor acute lymphoblastic leukemia with IG-MYC rearrangement",

abstract = "Rarely, immunophenotypically immature B-cell precursor acute lymphoblastic leukemia (BCP-ALL) carries an immunoglobulin-MYC rearrangement (IG-MYC-r). This can result in diagnostic confusion with Burkitt lymphoma/leukemia and use of individualized treatment schedules of unproven efficacy. Here we compare the molecular characteristics of these conditions and investigate historic clinical outcome data. We identified 90 cases registered in a national BCP-ALL clinical trial/registry. When present, diagnostic material underwent cytogenetic, exome, methylome and transcriptome analyses. The outcomes analyzed were 3-year event-free survival and overall survival. IG-MYC-r was identified in diverse cytogenetic backgrounds, co-existing with either established BCP-ALL-specific abnormalities (high hyperdiploidy, n=3; KMT2A-rearrangement, n=6; iAMP21, n=1; BCR-ABL1, n=1); BCL2/BCL6-rearrangements (n=15); or, most commonly, as the only defining feature (n=64). Within this final group, precursor-like V(D)J breakpoints predominated (8/9) and KRAS mutations were common (5/11). DNA methylation identified a cluster of V(D)J-rearranged cases, clearly distinct from Burkitt leukemia/lymphoma. Children with IG-MYC-r within that subgroup had a 3-year event-free survival of 47% and overall survival of 60%, representing a high-risk BCP-ALL. To develop effective management strategies this group of patients must be allowed access to contemporary, minimal residual disease-adapted, prospective clinical trial protocols.",

author = "Simon Bomken and Amir Enshaei and Schwalbe, {Edward C.} and Aneta Mikulasova and Yunfeng Dai and Masood Zaka and Fung, {Kent T.M.} and Matthew Bashton and Huezin Lim and Lisa Jones and Nefeli Karataraki and Emily Winterman and Cody Ashby and Andishe Attarbaschi and Yves Bertrand and Jutta Bradtke and Barbara Buldini and Burke, {G. A.Amos} and Giovanni Cazzaniga and Gudrun G{\"o}hring and {de Groot-Kruseman}, {Hesta A.} and Claudia Haferlach and Nigro, {Luca Lo} and Mayur Parihar and Adriana Plesa and Emma Seaford and Edwin Sonneveld and Sabine Strehl and {van der Velden}, {Vincent H.J.} and Vikki Rand and Hunger, {Stephen P.} and Harrison, {Christine J.} and Bacon, {Chris M.} and {van Delft}, {Frederik W.} and Loh, {Mignon L.} and John Moppett and Josef Vormoor and Walker, {Brian A.} and Moorman, {Anthony V.} and Russell, {Lisa J.}",

note = "Funding Information: We would like to thank those who provided financial support. Kay Kendall Leukaemia Fund (KKL515), Wellcome Trust Institutional Strategic Support Fund (204787/Z/16/Z), The Newcastle upon Tyne Hospitals NHS charity and KidsCan Children{\textquoteright}s Cancer Research and The Little Princess Trust (to LJR). LJR held a Newcastle University Research Fellowship and A.M. a Newcastle University Faculty Fellowship. SB was supported by The Sir Bobby Robson Foundation and an MRC Clinician Scientist Fellowship MR/S021590/1. COG funding was available through U10 CA98413 and U10 CA180899 (COG Statistics and Data Center grants), U24 CA114766 and U24-CA196173 (COG Specimen Banking). AVM and CJH were supported by Blood Cancer UK (15036) and Cancer Research UK (A21019, Moorman and Fielding). LLN was partially supported by MFAG 2009 – AIRC (Italian Association for Cancer Research) (Lo Nigro). VR was supported by a Bloodwise (formerly Leukaemia and Lymphoma Research) Senior Bennett Fellowship (#12005), the JGW Patterson Foundation and the Little Princess Trust. MZ was supported by North East Promenaders. GC was supported by the Italian Association for Cancer Research (Grant n.IG17593) and Comitato Maria Letizia Verga. Publisher Copyright: {\textcopyright}2023 Ferrata Storti Foundation.",

year = "2023",

month = mar,

doi = "10.3324/haematol.2021.280557",

language = "English",

volume = "108",

pages = "717--731",

journal = "Haematologica",

issn = "0390-6078",

publisher = "Ferrata Storti Foundation",

number = "3",

}

Bomken, S, Enshaei, A, Schwalbe, EC, Mikulasova, A, Dai, Y, Zaka, M, Fung, KTM, Bashton, M, Lim, H, Jones, L, Karataraki, N, Winterman, E, Ashby, C, Attarbaschi, A, Bertrand, Y, Bradtke, J, Buldini, B, Burke, GAA, Cazzaniga, G, Göhring, G, de Groot-Kruseman, HA, Haferlach, C, Nigro, LL, Parihar, M, Plesa, A, Seaford, E, Sonneveld, E, Strehl, S, van der Velden, VHJ, Rand, V, Hunger, SP, Harrison, CJ, Bacon, CM, van Delft, FW, Loh, ML, Moppett, J, Vormoor, J, Walker, BA, Moorman, AV & Russell, LJ 2023, 'Molecular characterization and clinical outcome of B-cell precursor acute lymphoblastic leukemia with IG-MYC rearrangement', Haematologica, vol. 108, no. 3, pp. 717-731. https://doi.org/10.3324/haematol.2021.280557

TY - JOUR

T1 - Molecular characterization and clinical outcome of B-cell precursor acute lymphoblastic leukemia with IG-MYC rearrangement

AU - Bomken, Simon

AU - Enshaei, Amir

AU - Schwalbe, Edward C.

AU - Mikulasova, Aneta

AU - Dai, Yunfeng

AU - Zaka, Masood

AU - Fung, Kent T.M.

AU - Bashton, Matthew

AU - Lim, Huezin

AU - Jones, Lisa

AU - Karataraki, Nefeli

AU - Winterman, Emily

AU - Ashby, Cody

AU - Attarbaschi, Andishe

AU - Bertrand, Yves

AU - Bradtke, Jutta

AU - Buldini, Barbara

AU - Burke, G. A.Amos

AU - Cazzaniga, Giovanni

AU - Göhring, Gudrun

AU - de Groot-Kruseman, Hesta A.

AU - Haferlach, Claudia

AU - Nigro, Luca Lo

AU - Parihar, Mayur

AU - Plesa, Adriana

AU - Seaford, Emma

AU - Sonneveld, Edwin

AU - Strehl, Sabine

AU - van der Velden, Vincent H.J.

AU - Rand, Vikki

AU - Hunger, Stephen P.

AU - Harrison, Christine J.

AU - Bacon, Chris M.

AU - van Delft, Frederik W.

AU - Loh, Mignon L.

AU - Moppett, John

AU - Vormoor, Josef

AU - Walker, Brian A.

AU - Moorman, Anthony V.

AU - Russell, Lisa J.

N1 - Funding Information: We would like to thank those who provided financial support. Kay Kendall Leukaemia Fund (KKL515), Wellcome Trust Institutional Strategic Support Fund (204787/Z/16/Z), The Newcastle upon Tyne Hospitals NHS charity and KidsCan Children’s Cancer Research and The Little Princess Trust (to LJR). LJR held a Newcastle University Research Fellowship and A.M. a Newcastle University Faculty Fellowship. SB was supported by The Sir Bobby Robson Foundation and an MRC Clinician Scientist Fellowship MR/S021590/1. COG funding was available through U10 CA98413 and U10 CA180899 (COG Statistics and Data Center grants), U24 CA114766 and U24-CA196173 (COG Specimen Banking). AVM and CJH were supported by Blood Cancer UK (15036) and Cancer Research UK (A21019, Moorman and Fielding). LLN was partially supported by MFAG 2009 – AIRC (Italian Association for Cancer Research) (Lo Nigro). VR was supported by a Bloodwise (formerly Leukaemia and Lymphoma Research) Senior Bennett Fellowship (#12005), the JGW Patterson Foundation and the Little Princess Trust. MZ was supported by North East Promenaders. GC was supported by the Italian Association for Cancer Research (Grant n.IG17593) and Comitato Maria Letizia Verga. Publisher Copyright: ©2023 Ferrata Storti Foundation.

PY - 2023/3

Y1 - 2023/3

N2 - Rarely, immunophenotypically immature B-cell precursor acute lymphoblastic leukemia (BCP-ALL) carries an immunoglobulin-MYC rearrangement (IG-MYC-r). This can result in diagnostic confusion with Burkitt lymphoma/leukemia and use of individualized treatment schedules of unproven efficacy. Here we compare the molecular characteristics of these conditions and investigate historic clinical outcome data. We identified 90 cases registered in a national BCP-ALL clinical trial/registry. When present, diagnostic material underwent cytogenetic, exome, methylome and transcriptome analyses. The outcomes analyzed were 3-year event-free survival and overall survival. IG-MYC-r was identified in diverse cytogenetic backgrounds, co-existing with either established BCP-ALL-specific abnormalities (high hyperdiploidy, n=3; KMT2A-rearrangement, n=6; iAMP21, n=1; BCR-ABL1, n=1); BCL2/BCL6-rearrangements (n=15); or, most commonly, as the only defining feature (n=64). Within this final group, precursor-like V(D)J breakpoints predominated (8/9) and KRAS mutations were common (5/11). DNA methylation identified a cluster of V(D)J-rearranged cases, clearly distinct from Burkitt leukemia/lymphoma. Children with IG-MYC-r within that subgroup had a 3-year event-free survival of 47% and overall survival of 60%, representing a high-risk BCP-ALL. To develop effective management strategies this group of patients must be allowed access to contemporary, minimal residual disease-adapted, prospective clinical trial protocols.

AB - Rarely, immunophenotypically immature B-cell precursor acute lymphoblastic leukemia (BCP-ALL) carries an immunoglobulin-MYC rearrangement (IG-MYC-r). This can result in diagnostic confusion with Burkitt lymphoma/leukemia and use of individualized treatment schedules of unproven efficacy. Here we compare the molecular characteristics of these conditions and investigate historic clinical outcome data. We identified 90 cases registered in a national BCP-ALL clinical trial/registry. When present, diagnostic material underwent cytogenetic, exome, methylome and transcriptome analyses. The outcomes analyzed were 3-year event-free survival and overall survival. IG-MYC-r was identified in diverse cytogenetic backgrounds, co-existing with either established BCP-ALL-specific abnormalities (high hyperdiploidy, n=3; KMT2A-rearrangement, n=6; iAMP21, n=1; BCR-ABL1, n=1); BCL2/BCL6-rearrangements (n=15); or, most commonly, as the only defining feature (n=64). Within this final group, precursor-like V(D)J breakpoints predominated (8/9) and KRAS mutations were common (5/11). DNA methylation identified a cluster of V(D)J-rearranged cases, clearly distinct from Burkitt leukemia/lymphoma. Children with IG-MYC-r within that subgroup had a 3-year event-free survival of 47% and overall survival of 60%, representing a high-risk BCP-ALL. To develop effective management strategies this group of patients must be allowed access to contemporary, minimal residual disease-adapted, prospective clinical trial protocols.

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U2 - 10.3324/haematol.2021.280557

DO - 10.3324/haematol.2021.280557

M3 - Article

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AN - SCOPUS:85149153876

SN - 0390-6078

VL - 108

SP - 717

EP - 731

JO - Haematologica

JF - Haematologica

IS - 3

ER -

Molecular characterization and clinical outcome of B-cell precursor acute lymphoblastic leukemia with IG-MYC rearrangement

Abstract

Bibliographical note

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