Epigenetic regulator genes direct lineage switching in MLL/AF4 leukemia

Ricky Tirtakusuma; Katarzyna Szoltysek; Paul Milne; Vasily V Grinev; Anetta Ptasinska; Paulynn S 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; Shan Lin; Mark Wunderlich; Janine Stutterheim; Alexander Komkov; Elena Zerkalenkova; Paul Evans; Hesta McNeill; Alex Elder; Natalia Martinez-Soria; Sarah E Fordham; Yuzhe Shi; Lisa J Russell; Deepali Pal; Alex 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 Schewe; Yulia Olshanskaya; Michael J Thirman; Peter N Cockerill; James C Mulloy; Helen J Blair; Josef Vormoor; James M Allan; Constanze Bonifer; Olaf Heidenreich; Simon Bomken

doi:10.1182/blood.2021015036

Epigenetic regulator genes direct lineage switching in MLL/AF4 leukemia

Ricky Tirtakusuma^*, Katarzyna Szoltysek, Paul Milne, Vasily V Grinev, Anetta Ptasinska, Paulynn S 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, Shan Lin, Mark WunderlichJanine Stutterheim, Alexander Komkov, Elena Zerkalenkova, Paul Evans, Hesta McNeill, Alex Elder, Natalia Martinez-Soria, Sarah E Fordham, Yuzhe Shi, Lisa J Russell, Deepali Pal, Alex 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 Schewe, Yulia Olshanskaya, Michael J Thirman, Peter N Cockerill, James C Mulloy, Helen J Blair, Josef Vormoor, James M Allan, Constanze Bonifer, Olaf Heidenreich, Simon Bomken

^*Corresponding author for this work

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

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Abstract

The fusion gene MLL/AF4 defines a high-risk subtype of pro-B acute lymphoblastic leukemia. Relapse can be associated with a lineage switch from acute lymphoblastic to acute myeloid leukemia, resulting in poor clinical outcomes caused by resistance to chemotherapies and immunotherapies. In this study, the myeloid relapses shared oncogene fusion breakpoints with their matched lymphoid presentations and originated from various 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 programs, 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. Perturbation of CHD4 alone or in combination with other mutated epigenetic modifiers induces myeloid gene expression in MLL/AF4+ cell models, indicating that lineage switching in MLL/AF4 leukemia is driven and maintained by disrupted epigenetic regulation.

Original language	English
Pages (from-to)	1875-1890
Number of pages	16
Journal	Blood
Volume	140
Issue number	17
DOIs	https://doi.org/10.1182/blood.2021015036
Publication status	Published - 27 Oct 2022

Keywords

Chromatin
Epigenesis, Genetic
Genes, Regulator
Humans
Myeloid-Lymphoid Leukemia Protein/genetics
Oncogene Proteins, Fusion/genetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics

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

blood_bld-2021-015036-mainFinal published version, 3.27 MBLicence: CC BY-NC-ND

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Tirtakusuma, R., Szoltysek, K., Milne, P., Grinev, V. 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, E. K., Lin, S., ... Bomken, S. (2022). Epigenetic regulator genes direct lineage switching in MLL/AF4 leukemia. Blood, 140(17), 1875-1890. https://doi.org/10.1182/blood.2021015036

@article{ff7cab114d1a4f8b8e46ae13fc890a5f,

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

abstract = "The fusion gene MLL/AF4 defines a high-risk subtype of pro-B acute lymphoblastic leukemia. Relapse can be associated with a lineage switch from acute lymphoblastic to acute myeloid leukemia, resulting in poor clinical outcomes caused by resistance to chemotherapies and immunotherapies. In this study, the myeloid relapses shared oncogene fusion breakpoints with their matched lymphoid presentations and originated from various 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 programs, 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. Perturbation of CHD4 alone or in combination with other mutated epigenetic modifiers induces myeloid gene expression in MLL/AF4+ cell models, indicating that lineage switching in MLL/AF4 leukemia is driven and maintained by disrupted epigenetic regulation.",

keywords = "Chromatin, Epigenesis, Genetic, Genes, Regulator, Humans, Myeloid-Lymphoid Leukemia Protein/genetics, Oncogene Proteins, Fusion/genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics",

author = "Ricky Tirtakusuma and Katarzyna Szoltysek and Paul Milne and Grinev, {Vasily V} and Anetta Ptasinska and Chin, {Paulynn S} 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, {Elizabeth K} and Shan Lin and Mark Wunderlich and Janine Stutterheim and Alexander Komkov and Elena Zerkalenkova and Paul Evans and Hesta McNeill and Alex Elder and Natalia Martinez-Soria and Fordham, {Sarah E} and Yuzhe Shi and Russell, {Lisa J} and Deepali Pal and Alex Smith 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 Denis Schewe and Yulia Olshanskaya and Thirman, {Michael J} and Cockerill, {Peter N} and Mulloy, {James C} and Blair, {Helen J} and Josef Vormoor and Allan, {James M} and Constanze Bonifer and Olaf Heidenreich and Simon Bomken",

note = "Funding Information: The authors thank Jon Coxhead and Raf Hussain (Newcastle University Core Genomics Facility) and Marc van Tuil (Princess Maxima Center Diagnostic department) for development of sequencing strategies; the Newcastle University Flow Cytometry Core Facility and Tomasz Poplonski (Princess Maxima Center Flow Cytometry Core Facility) for assistance with the generation of flow cytometry data and cell sorting strategies; the Newcastle University Bioinformatics Support Unit for helping to develop the analysis approach for sequencing data; and Monique den Boer, Frank van Leeuwen, and Ronald Stam for critically reading the manuscript. This study was supported by a Cancer Research UK Centre Studentship (C27826/A17312) and Newcastle University Overseas Research Scholarship (R.T.); a CRUK program grant (J.V. O.H.) (C27943/A12788); a Kika programme grant (329) (O.H. J.V.); grants from the North of England Children's Cancer Research Fund (O.H. J.V. S.B.); Bloodwise grants 12055 and 15005 (O.H.); and a grant from the Kay Kendall Leukaemia Fund (KKL1142) (O.H.). S.B. was supported by an NIHR Academic Clinical Lectureship (CL-2012-01-002), the Sir Bobby Robson Foundation Clinical Fellowship, and a Medical Research Council Clinician Scientist Fellowship (MR/S021590/1). Work in C.B./P.N.C.{\textquoteright}s laboratory was funded by a programme grant from Bloodwise (15001). Work in J.M.A.{\textquoteright}s laboratory was funded by a programme grant from Bloodwise (13044). E.Z. was supported by a Russian Foundation for Basic Research (RFBR) grant (17-29-06052). Research in the V.V.G. laboratory was supported in part by the Ministry of Education of the Republic of Belarus, grant 3.04.3. Research in A.K.{\textquoteright}s laboratory was supported by an Russell Sage Foundation (RSF) grant (20-75-10091). The study made use of data generated by the St Jude Children's Research Hospital-Washington University Pediatric Cancer Genome Project and the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative, phs000218, managed by the National Cancer Institute (supplemental Methods). Contribution: O.H. S. Bomken, and C.B. conceived the study; O.H. C.B. R.T. K.S. P.M. S. Bomken, A.P. C.M. A.K. Z.K. J.B. V.B. R.M. J.V. J.M.A. and S.L. developed the methodology; S.N. J.Y.H.-K. V.V.G. A.K. D.W. and P.C. were responsible for the software programming; S.N. M.A. J.H.K. V.V.G. A.K. D.W. P.C. P.K. C.B. and O.H. performed the formal analysis; R.T. K.S. P.M. A.P. C.M. P.S.C. H.J.B. S.G.K. A.K. S.A.A. M.R.I. E.K.S. P.E. H.M. A.E. N.M.-S. S.E.F. Y.S. D.P. and P.C. performed the investigations; J.S. F.V. E.Z. A.S. J.C.M. L.J.R. C.E. O.A.H. S. Bailey, R.S. N.M. M.C. V.B. R.M. M.W. C.J.H. C.A.C. D.S. Y.O. M.J.T. P.N.C. J.C.M. M.H. C.B. and O.H. obtained the resources; S.N. D.W. and P.C. were responsible for data curation; S. Bomken, O.H. C.B. R.T. and K.S. wrote the manuscript; O.H. S. Bomken, J.M.A. J.V. and C.B. supervised the study; and O.H. J.V. S. Bomken, C.B. P.N.C. J.M.A. and E.Z. acquired the funding. Funding Information: This study was supported by a Cancer Research UK Centre Studentship (C27826/A17312) and Newcastle University Overseas Research Scholarship (R.T.); a CRUK program grant (J.V., O.H.) (C27943/A12788); a Kika programme grant (329) (O.H., J.V.); grants from the North of England Children{\textquoteright}s Cancer Research Fund (O.H., J.V., S.B.); Bloodwise grants 12055 and 15005 (O.H.); and a grant from the Kay Kendall Leukaemia Fund (KKL1142) (O.H.). S.B. was supported by an NIHR Academic Clinical Lectureship (CL-2012-01-002), the Sir Bobby Robson Foundation Clinical Fellowship, and a Medical Research Council Clinician Scientist Fellowship (MR/S021590/1). Work in C.B./P.N.C.{\textquoteright}s laboratory was funded by a programme grant from Bloodwise (15001). Work in J.M.A.{\textquoteright}s laboratory was funded by a programme grant from Bloodwise (13044). E.Z. was supported by a Russian Foundation for Basic Research (RFBR) grant (17-29-06052). Research in the V.V.G. laboratory was supported in part by the Ministry of Education of the Republic of Belarus , grant 3.04.3. Research in A.K.{\textquoteright}s laboratory was supported by an Russell Sage Foundation (RSF) grant (20-75-10091). The study made use of data generated by the St Jude Children{\textquoteright}s Research Hospital-Washington University Pediatric Cancer Genome Project and the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative, phs000218, managed by the National Cancer Institute ( supplemental Methods ). Publisher Copyright: {\textcopyright} 2022 The American Society of Hematology",

year = "2022",

month = oct,

day = "27",

doi = "10.1182/blood.2021015036",

language = "English",

volume = "140",

pages = "1875--1890",

journal = "Blood",

issn = "0006-4971",

publisher = "American Society of Hematology",

number = "17",

}

Tirtakusuma, R, Szoltysek, K, Milne, P, Grinev, VV, 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, EK, Lin, S, Wunderlich, M, Stutterheim, J, Komkov, A, Zerkalenkova, E, Evans, P, McNeill, H, Elder, A, Martinez-Soria, N, Fordham, SE, Shi, Y, Russell, LJ, Pal, D, Smith, A, 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, D, Olshanskaya, Y, Thirman, MJ, Cockerill, PN, Mulloy, JC, Blair, HJ, Vormoor, J, Allan, JM, Bonifer, C, Heidenreich, O & Bomken, S 2022, 'Epigenetic regulator genes direct lineage switching in MLL/AF4 leukemia', Blood, vol. 140, no. 17, pp. 1875-1890. https://doi.org/10.1182/blood.2021015036

TY - JOUR

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

AU - Tirtakusuma, Ricky

AU - Szoltysek, Katarzyna

AU - Milne, Paul

AU - Grinev, Vasily V

AU - Ptasinska, Anetta

AU - Chin, Paulynn S

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, Elizabeth K

AU - Lin, Shan

AU - Wunderlich, Mark

AU - Stutterheim, Janine

AU - Komkov, Alexander

AU - Zerkalenkova, Elena

AU - Evans, Paul

AU - McNeill, Hesta

AU - Elder, Alex

AU - Martinez-Soria, Natalia

AU - Fordham, Sarah E

AU - Shi, Yuzhe

AU - Russell, Lisa J

AU - Pal, Deepali

AU - Smith, Alex

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

AU - Olshanskaya, Yulia

AU - Thirman, Michael J

AU - Cockerill, Peter N

AU - Mulloy, James C

AU - Blair, Helen J

AU - Vormoor, Josef

AU - Allan, James M

AU - Bonifer, Constanze

AU - Heidenreich, Olaf

AU - Bomken, Simon

N1 - Funding Information: The authors thank Jon Coxhead and Raf Hussain (Newcastle University Core Genomics Facility) and Marc van Tuil (Princess Maxima Center Diagnostic department) for development of sequencing strategies; the Newcastle University Flow Cytometry Core Facility and Tomasz Poplonski (Princess Maxima Center Flow Cytometry Core Facility) for assistance with the generation of flow cytometry data and cell sorting strategies; the Newcastle University Bioinformatics Support Unit for helping to develop the analysis approach for sequencing data; and Monique den Boer, Frank van Leeuwen, and Ronald Stam for critically reading the manuscript. This study was supported by a Cancer Research UK Centre Studentship (C27826/A17312) and Newcastle University Overseas Research Scholarship (R.T.); a CRUK program grant (J.V. O.H.) (C27943/A12788); a Kika programme grant (329) (O.H. J.V.); grants from the North of England Children's Cancer Research Fund (O.H. J.V. S.B.); Bloodwise grants 12055 and 15005 (O.H.); and a grant from the Kay Kendall Leukaemia Fund (KKL1142) (O.H.). S.B. was supported by an NIHR Academic Clinical Lectureship (CL-2012-01-002), the Sir Bobby Robson Foundation Clinical Fellowship, and a Medical Research Council Clinician Scientist Fellowship (MR/S021590/1). Work in C.B./P.N.C.’s laboratory was funded by a programme grant from Bloodwise (15001). Work in J.M.A.’s laboratory was funded by a programme grant from Bloodwise (13044). E.Z. was supported by a Russian Foundation for Basic Research (RFBR) grant (17-29-06052). Research in the V.V.G. laboratory was supported in part by the Ministry of Education of the Republic of Belarus, grant 3.04.3. Research in A.K.’s laboratory was supported by an Russell Sage Foundation (RSF) grant (20-75-10091). The study made use of data generated by the St Jude Children's Research Hospital-Washington University Pediatric Cancer Genome Project and the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative, phs000218, managed by the National Cancer Institute (supplemental Methods). Contribution: O.H. S. Bomken, and C.B. conceived the study; O.H. C.B. R.T. K.S. P.M. S. Bomken, A.P. C.M. A.K. Z.K. J.B. V.B. R.M. J.V. J.M.A. and S.L. developed the methodology; S.N. J.Y.H.-K. V.V.G. A.K. D.W. and P.C. were responsible for the software programming; S.N. M.A. J.H.K. V.V.G. A.K. D.W. P.C. P.K. C.B. and O.H. performed the formal analysis; R.T. K.S. P.M. A.P. C.M. P.S.C. H.J.B. S.G.K. A.K. S.A.A. M.R.I. E.K.S. P.E. H.M. A.E. N.M.-S. S.E.F. Y.S. D.P. and P.C. performed the investigations; J.S. F.V. E.Z. A.S. J.C.M. L.J.R. C.E. O.A.H. S. Bailey, R.S. N.M. M.C. V.B. R.M. M.W. C.J.H. C.A.C. D.S. Y.O. M.J.T. P.N.C. J.C.M. M.H. C.B. and O.H. obtained the resources; S.N. D.W. and P.C. were responsible for data curation; S. Bomken, O.H. C.B. R.T. and K.S. wrote the manuscript; O.H. S. Bomken, J.M.A. J.V. and C.B. supervised the study; and O.H. J.V. S. Bomken, C.B. P.N.C. J.M.A. and E.Z. acquired the funding. Funding Information: This study was supported by a Cancer Research UK Centre Studentship (C27826/A17312) and Newcastle University Overseas Research Scholarship (R.T.); a CRUK program grant (J.V., O.H.) (C27943/A12788); a Kika programme grant (329) (O.H., J.V.); grants from the North of England Children’s Cancer Research Fund (O.H., J.V., S.B.); Bloodwise grants 12055 and 15005 (O.H.); and a grant from the Kay Kendall Leukaemia Fund (KKL1142) (O.H.). S.B. was supported by an NIHR Academic Clinical Lectureship (CL-2012-01-002), the Sir Bobby Robson Foundation Clinical Fellowship, and a Medical Research Council Clinician Scientist Fellowship (MR/S021590/1). Work in C.B./P.N.C.’s laboratory was funded by a programme grant from Bloodwise (15001). Work in J.M.A.’s laboratory was funded by a programme grant from Bloodwise (13044). E.Z. was supported by a Russian Foundation for Basic Research (RFBR) grant (17-29-06052). Research in the V.V.G. laboratory was supported in part by the Ministry of Education of the Republic of Belarus , grant 3.04.3. Research in A.K.’s laboratory was supported by an Russell Sage Foundation (RSF) grant (20-75-10091). The study made use of data generated by the St Jude Children’s Research Hospital-Washington University Pediatric Cancer Genome Project and the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative, phs000218, managed by the National Cancer Institute ( supplemental Methods ). Publisher Copyright: © 2022 The American Society of Hematology

PY - 2022/10/27

Y1 - 2022/10/27

N2 - The fusion gene MLL/AF4 defines a high-risk subtype of pro-B acute lymphoblastic leukemia. Relapse can be associated with a lineage switch from acute lymphoblastic to acute myeloid leukemia, resulting in poor clinical outcomes caused by resistance to chemotherapies and immunotherapies. In this study, the myeloid relapses shared oncogene fusion breakpoints with their matched lymphoid presentations and originated from various 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 programs, 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. Perturbation of CHD4 alone or in combination with other mutated epigenetic modifiers induces myeloid gene expression in MLL/AF4+ cell models, indicating that lineage switching in MLL/AF4 leukemia is driven and maintained by disrupted epigenetic regulation.

AB - The fusion gene MLL/AF4 defines a high-risk subtype of pro-B acute lymphoblastic leukemia. Relapse can be associated with a lineage switch from acute lymphoblastic to acute myeloid leukemia, resulting in poor clinical outcomes caused by resistance to chemotherapies and immunotherapies. In this study, the myeloid relapses shared oncogene fusion breakpoints with their matched lymphoid presentations and originated from various 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 programs, 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. Perturbation of CHD4 alone or in combination with other mutated epigenetic modifiers induces myeloid gene expression in MLL/AF4+ cell models, indicating that lineage switching in MLL/AF4 leukemia is driven and maintained by disrupted epigenetic regulation.

KW - Chromatin

KW - Epigenesis, Genetic

KW - Genes, Regulator

KW - Humans

KW - Myeloid-Lymphoid Leukemia Protein/genetics

KW - Oncogene Proteins, Fusion/genetics

KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics

UR - http://www.scopus.com/inward/record.url?scp=85138096220&partnerID=8YFLogxK

U2 - 10.1182/blood.2021015036

DO - 10.1182/blood.2021015036

M3 - Article

C2 - 35839448

SN - 0006-4971

VL - 140

SP - 1875

EP - 1890

JO - Blood

JF - Blood

IS - 17

ER -

Epigenetic regulator genes direct lineage switching in MLL/AF4 leukemia

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