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 Gohring; 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 GohringHesta 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

Research related

Research output: Contribution to journal › Article › peer-review

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
DOIs	https://doi.org/10.3324/haematol.2021.280557
Publication status	Published - Mar 2023

Keywords

Child
Humans
Burkitt Lymphoma/diagnosis
Prospective Studies
Immunoglobulins/genetics
Gene Rearrangement
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/diagnosis

Access to Document

10.3324/haematol.2021.280557

Cite this

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{ab530e27718f40ca9458fb98920f8f09,

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.",

keywords = "Child, Humans, Burkitt Lymphoma/diagnosis, Prospective Studies, Immunoglobulins/genetics, Gene Rearrangement, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/diagnosis",

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 Gohring 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}",

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, Gohring, 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 - Gohring, 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

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.

KW - Child

KW - Humans

KW - Burkitt Lymphoma/diagnosis

KW - Prospective Studies

KW - Immunoglobulins/genetics

KW - Gene Rearrangement

KW - Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/diagnosis

UR - https://www.mendeley.com/catalogue/612a0e6c-dac5-3fbb-bdbc-60e0259b90d4/

U2 - 10.3324/haematol.2021.280557

DO - 10.3324/haematol.2021.280557

M3 - Article

C2 - 35484682

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

Keywords

Access to Document

Fingerprint

Cite this