Epigenetic regulator genes direct lineage switching in MLL/AF4 leukaemia

Ricky Tirtakusuma; Katarzyna Szoltysek; Paul Milne; Vasily Grinev; Anetta Ptasinska; Paulynn Suyin Chin; Claus Meyer; Sirintra Nakjang; Jayne Y Hehir-Kwa; Daniel Williamson; Pierre Cauchy; Peter Keane; Salam a Assi; Minoo Ashtiani; Sophie G. Kellaway; Maria R Imperato; Fotini Vogiatzi; Elizabeth K Schweighart-James; Shan Lin; Mark Wunderlich; Janine Stutterheim; Alexander Komkov; PhD Zerkalenkova Elena; Paul Evans; Hesta Varey McNeill; Alex Elder; Natalia Martínez-Soria; Sarah E Fordham; Yuzhe Shi; Lisa J Russell; Deepali Pal; Alexandra G Smith; Zoya Kingsbury; Jennifer Becq; Cornelia Eckert; Oskar A Haas; Peter Carey; Simon Bailey; Roderick Skinner; Natalia Miakova; Matthew Collin; Venetia Bigley; Muzlifah Haniffa; Rolf Marschalek; Christine J Harrison; Catherine A Cargo; Denis Martin Schewe; Yulia Olshanskaya; Michael J. Thirman; Peter N Cockerill

doi:10.1182/blood.2021015036

Epigenetic regulator genes direct lineage switching in MLL/AF4 leukaemia

Ricky Tirtakusuma, Katarzyna Szoltysek, Paul Milne, Vasily Grinev, Anetta Ptasinska, Paulynn Suyin Chin, Claus Meyer, Sirintra Nakjang, Jayne Y Hehir-Kwa, Daniel Williamson, Pierre Cauchy, Peter Keane, Salam a Assi, Minoo Ashtiani, Sophie G. Kellaway, Maria R Imperato, Fotini Vogiatzi, Elizabeth K Schweighart-James, Shan Lin, Mark WunderlichJanine Stutterheim, Alexander Komkov, PhD Zerkalenkova Elena, Paul Evans, Hesta Varey McNeill, Alex Elder, Natalia Martínez-Soria, Sarah E Fordham, Yuzhe Shi, Lisa J Russell, Deepali Pal, Alexandra G Smith, Zoya Kingsbury, Jennifer Becq, Cornelia Eckert, Oskar A Haas, Peter Carey, Simon Bailey, Roderick Skinner, Natalia Miakova, Matthew Collin, Venetia Bigley, Muzlifah Haniffa, Rolf Marschalek, Christine J Harrison, Catherine A Cargo, Denis Martin Schewe, Yulia Olshanskaya, Michael J. Thirman, Peter N Cockerill

Health Sciences

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

Abstract

The fusion gene MLL/AF4 defines a high-risk subtype of pro-B acute lymphoblastic leukaemia. Relapse can be associated with a lineage switch from acute lymphoblastic to acute myeloid leukaemia resulting in poor clinical outcomes due to resistance towards chemo- and immuno-therapies. Here we show that the myeloid relapses share oncogene fusion breakpoints with their matched lymphoid presentations and can originate from varying differentiation stages from immature progenitors through to committed B-cell precursors. Lineage switching is linked to substantial changes in chromatin accessibility and rewiring of transcriptional programmes, including alternative splicing. These findings indicate that the execution and maintenance of lymphoid lineage differentiation is impaired. The relapsed myeloid phenotype is recurrently associated with the altered expression, splicing or mutation of chromatin modifiers, including CHD4 coding for the ATPase/helicase of the nucleosome remodelling and deacetylation complex, NuRD. Perturbation of CHD4 alone or in combination with other mutated epigenetic modifiers induces myeloid gene expression in MLL/AF4-positive cell models indicating that lineage switching in MLL/AF4 leukaemia is driven and maintained by disrupted epigenetic regulation.

Original language	English
Article number	blood.2021015036
Pages (from-to)	1875-1890
Number of pages	16
Journal	Blood
Volume	40
Issue number	17
Early online date	27 Oct 2022
DOIs	https://doi.org/10.1182/blood.2021015036
Publication status	E-pub ahead of print - 27 Oct 2022

Bibliographical note

© 2022 by The American Society of Hematology.
blood.2021015036

Access to Document

10.1182/blood.2021015036Licence: CC BY-NC-ND

blood.2021015036
© 2022 by The American Society of Hematology.
Accepted author manuscript, 2.3 MBLicence: CC BY-NC-ND

Cite this

Tirtakusuma, R., Szoltysek, K., Milne, P., Grinev, V., Ptasinska, A., Chin, P. S., Meyer, C., Nakjang, S., Hehir-Kwa, J. Y., Williamson, D., Cauchy, P., Keane, P., Assi, S. A., Ashtiani, M., Kellaway, S. G., Imperato, M. R., Vogiatzi, F., Schweighart-James, E. K., Lin, S., ... Cockerill, P. N. (2022). Epigenetic regulator genes direct lineage switching in MLL/AF4 leukaemia. Blood, 40(17), 1875-1890. Article blood.2021015036. Advance online publication. https://doi.org/10.1182/blood.2021015036

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title = "Epigenetic regulator genes direct lineage switching in MLL/AF4 leukaemia",

abstract = "The fusion gene MLL/AF4 defines a high-risk subtype of pro-B acute lymphoblastic leukaemia. Relapse can be associated with a lineage switch from acute lymphoblastic to acute myeloid leukaemia resulting in poor clinical outcomes due to resistance towards chemo- and immuno-therapies. Here we show that the myeloid relapses share oncogene fusion breakpoints with their matched lymphoid presentations and can originate from varying differentiation stages from immature progenitors through to committed B-cell precursors. Lineage switching is linked to substantial changes in chromatin accessibility and rewiring of transcriptional programmes, including alternative splicing. These findings indicate that the execution and maintenance of lymphoid lineage differentiation is impaired. The relapsed myeloid phenotype is recurrently associated with the altered expression, splicing or mutation of chromatin modifiers, including CHD4 coding for the ATPase/helicase of the nucleosome remodelling and deacetylation complex, NuRD. Perturbation of CHD4 alone or in combination with other mutated epigenetic modifiers induces myeloid gene expression in MLL/AF4-positive cell models indicating that lineage switching in MLL/AF4 leukaemia is driven and maintained by disrupted epigenetic regulation.",

author = "Ricky Tirtakusuma and Katarzyna Szoltysek and Paul Milne and Vasily Grinev and Anetta Ptasinska and Chin, {Paulynn Suyin} and Claus Meyer and Sirintra Nakjang and Hehir-Kwa, {Jayne Y} and Daniel Williamson and Pierre Cauchy and Peter Keane and Assi, {Salam a} and Minoo Ashtiani and Kellaway, {Sophie G.} and Imperato, {Maria R} and Fotini Vogiatzi and Schweighart-James, {Elizabeth K} and Shan Lin and Mark Wunderlich and Janine Stutterheim and Alexander Komkov and {Zerkalenkova Elena}, PhD and Paul Evans and McNeill, {Hesta Varey} and Alex Elder and Natalia Mart{\'i}nez-Soria and Fordham, {Sarah E} and Yuzhe Shi and Russell, {Lisa J} and Deepali Pal and Smith, {Alexandra G} and Zoya Kingsbury and Jennifer Becq and Cornelia Eckert and Haas, {Oskar A} and Peter Carey and Simon Bailey and Roderick Skinner and Natalia Miakova and Matthew Collin and Venetia Bigley and Muzlifah Haniffa and Rolf Marschalek and Harrison, {Christine J} and Cargo, {Catherine A} and Schewe, {Denis Martin} and Yulia Olshanskaya and Thirman, {Michael J.} and Cockerill, {Peter N}",

note = "{\textcopyright} 2022 by The American Society of Hematology. blood.2021015036",

year = "2022",

month = oct,

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doi = "10.1182/blood.2021015036",

language = "English",

volume = "40",

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journal = "Blood",

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Tirtakusuma, R, Szoltysek, K, Milne, P, Grinev, V, Ptasinska, A, Chin, PS, Meyer, C, Nakjang, S, Hehir-Kwa, JY, Williamson, D, Cauchy, P, Keane, P, Assi, SA, Ashtiani, M, Kellaway, SG, Imperato, MR, Vogiatzi, F, Schweighart-James, EK, Lin, S, Wunderlich, M, Stutterheim, J, Komkov, A, Zerkalenkova Elena, P, Evans, P, McNeill, HV, Elder, A, Martínez-Soria, N, Fordham, SE, Shi, Y, Russell, LJ, Pal, D, Smith, AG, Kingsbury, Z, Becq, J, Eckert, C, Haas, OA, Carey, P, Bailey, S, Skinner, R, Miakova, N, Collin, M, Bigley, V, Haniffa, M, Marschalek, R, Harrison, CJ, Cargo, CA, Schewe, DM, Olshanskaya, Y, Thirman, MJ & Cockerill, PN 2022, 'Epigenetic regulator genes direct lineage switching in MLL/AF4 leukaemia', Blood, vol. 40, no. 17, blood.2021015036, pp. 1875-1890. https://doi.org/10.1182/blood.2021015036

TY - JOUR

T1 - Epigenetic regulator genes direct lineage switching in MLL/AF4 leukaemia

AU - Tirtakusuma, Ricky

AU - Szoltysek, Katarzyna

AU - Milne, Paul

AU - Grinev, Vasily

AU - Ptasinska, Anetta

AU - Chin, Paulynn Suyin

AU - Meyer, Claus

AU - Nakjang, Sirintra

AU - Hehir-Kwa, Jayne Y

AU - Williamson, Daniel

AU - Cauchy, Pierre

AU - Keane, Peter

AU - Assi, Salam a

AU - Ashtiani, Minoo

AU - Kellaway, Sophie G.

AU - Imperato, Maria R

AU - Vogiatzi, Fotini

AU - Schweighart-James, Elizabeth K

AU - Lin, Shan

AU - Wunderlich, Mark

AU - Stutterheim, Janine

AU - Komkov, Alexander

AU - Zerkalenkova Elena, PhD

AU - Evans, Paul

AU - McNeill, Hesta Varey

AU - Elder, Alex

AU - Martínez-Soria, Natalia

AU - Fordham, Sarah E

AU - Shi, Yuzhe

AU - Russell, Lisa J

AU - Pal, Deepali

AU - Smith, Alexandra G

AU - Kingsbury, Zoya

AU - Becq, Jennifer

AU - Eckert, Cornelia

AU - Haas, Oskar A

AU - Carey, Peter

AU - Bailey, Simon

AU - Skinner, Roderick

AU - Miakova, Natalia

AU - Collin, Matthew

AU - Bigley, Venetia

AU - Haniffa, Muzlifah

AU - Marschalek, Rolf

AU - Harrison, Christine J

AU - Cargo, Catherine A

AU - Schewe, Denis Martin

AU - Olshanskaya, Yulia

AU - Thirman, Michael J.

AU - Cockerill, Peter N

PY - 2022/10/27

Y1 - 2022/10/27

N2 - The fusion gene MLL/AF4 defines a high-risk subtype of pro-B acute lymphoblastic leukaemia. Relapse can be associated with a lineage switch from acute lymphoblastic to acute myeloid leukaemia resulting in poor clinical outcomes due to resistance towards chemo- and immuno-therapies. Here we show that the myeloid relapses share oncogene fusion breakpoints with their matched lymphoid presentations and can originate from varying differentiation stages from immature progenitors through to committed B-cell precursors. Lineage switching is linked to substantial changes in chromatin accessibility and rewiring of transcriptional programmes, including alternative splicing. These findings indicate that the execution and maintenance of lymphoid lineage differentiation is impaired. The relapsed myeloid phenotype is recurrently associated with the altered expression, splicing or mutation of chromatin modifiers, including CHD4 coding for the ATPase/helicase of the nucleosome remodelling and deacetylation complex, NuRD. Perturbation of CHD4 alone or in combination with other mutated epigenetic modifiers induces myeloid gene expression in MLL/AF4-positive cell models indicating that lineage switching in MLL/AF4 leukaemia is driven and maintained by disrupted epigenetic regulation.

AB - The fusion gene MLL/AF4 defines a high-risk subtype of pro-B acute lymphoblastic leukaemia. Relapse can be associated with a lineage switch from acute lymphoblastic to acute myeloid leukaemia resulting in poor clinical outcomes due to resistance towards chemo- and immuno-therapies. Here we show that the myeloid relapses share oncogene fusion breakpoints with their matched lymphoid presentations and can originate from varying differentiation stages from immature progenitors through to committed B-cell precursors. Lineage switching is linked to substantial changes in chromatin accessibility and rewiring of transcriptional programmes, including alternative splicing. These findings indicate that the execution and maintenance of lymphoid lineage differentiation is impaired. The relapsed myeloid phenotype is recurrently associated with the altered expression, splicing or mutation of chromatin modifiers, including CHD4 coding for the ATPase/helicase of the nucleosome remodelling and deacetylation complex, NuRD. Perturbation of CHD4 alone or in combination with other mutated epigenetic modifiers induces myeloid gene expression in MLL/AF4-positive cell models indicating that lineage switching in MLL/AF4 leukaemia is driven and maintained by disrupted epigenetic regulation.

U2 - 10.1182/blood.2021015036

DO - 10.1182/blood.2021015036

M3 - Article

SN - 0006-4971

VL - 40

SP - 1875

EP - 1890

JO - Blood

JF - Blood

IS - 17

M1 - blood.2021015036

ER -