ArticleBlood2022
Epigenetic regulator genes direct lineage switching in MLL/AF4 leukemia.
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Article in Blood, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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43citing papers in PubMed
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43 citing papers in PubMed, 64 citations in OpenAlex.
- Lineage switch in leukemia and lymphoma: case reports and molecular and cellular mechanisms.Blood neoplasia · 2026Review
- MLL-AF9 expression levels do not instruct lineage fate.Haematologica · 2026Article
- Plasticity under pressure: biology and detection of lineage switch in acute leukemia.Leukemia · 2026Review
- Histiocytosis development and clinical variation through the lens of genomics.The Journal of pathology · 2026Review
- A genomic and epigenomic lens into the biology of acute lymphoblastic leukaemia.Nature reviews. Cancer · 2026Review
- Antigen Pressure, Clonal Evolution, and Lineage Plasticity in B-Cell Acute Lymphoblastic Leukemia: Resistance Biology in the Immunotherapy Era.Current hematologic malignancy reports · 2026Review
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- Co-option of lineage plasticity as a hallmark of multipotent acute leukemias.Blood neoplasia · 2026Review
- Epigenetics as a mechanism of lineage extinction and relapse of B-cell lymphoma treated with CD19 CAR T-cell therapy.Blood neoplasia · 2026Article
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- Case Report: Immune-driven clonal selection underlying lineage switch from B-Precursor acute lymphoblastic leukemia to acute myeloid leukemia following inotuzumab ozogamicin.Frontiers in immunology · 2026Article
- CD19-negative relapse after CAR-T cell therapy: mechanisms of antigen escape and lineage switch.Frontiers in immunology · 2026Review
- Suppressing t(4;11) Acute Leukemia by Lipopolymer Nanoparticle Delivery of siRNA Targeting KMT2A::AFF1 with Enhanced Extrahepatic Delivery.Advanced healthcare materials · 2025Article
- Review
- Multi-omics analysis identifies an M-MDSC-like immunosuppressive phenotype in lineage-switched AML with KMT2A rearrangement.Nature communications · 2025Article
- Article
- Multipotent lineage potential in B cell acute lymphoblastic leukemia is associated with distinct cellular origins and clinical features.Nature cancer · 2025Article
- A shadow in the treatment of acute leukemia: lineage switch.Blood science (Baltimore, Md.) · 2025Review
- Fusion-specific chromatin profiles mediate transcriptional heterogeneity in MLL-rearranged acute lymphoblastic leukemia.Blood advances · 2025Article
- The dynamic evolution of lineage switch under CD19 CAR-T treatment in non-KMT2A rearranged B-ALL patients.Leukemia · 2025Article
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Authors and funding
57 authors at 17 institutions in 8 countries.
Ricky TirtakusumaWolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
Katarzyna SzoltysekWolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.ORCID 0000-0003-4379-5221
Paul MilneTranslational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.ORCID 0000-0002-8278-0463
Vasily V GrinevDepartment of Genetics, the Faculty of Biology, Belarusian State University, Minsk, Republic of Belarus.ORCID 0000-0001-9981-7333
Anetta PtasinskaInstitute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.
Paulynn S ChinInstitute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.ORCID 0000-0003-1600-3508
Claus MeyerInstitute of Pharmaceutical Biology/DCAL, Goethe-University, Frankfurt/Main, Germany.
Sirintra NakjangWolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
Jayne Y Hehir-KwaPrincess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands.ORCID 0000-0003-0837-304X
Daniel WilliamsonWolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
Pierre CauchyInstitute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.
Peter KeaneInstitute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.
Salam A AssiInstitute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.
Minoo AshtianiPrincess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands.ORCID 0000-0002-2853-363X
Sophie G KellawayInstitute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.ORCID 0000-0002-4011-7460
Maria R ImperatoInstitute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.
Fotini VogiatziALL-BFM Study Group, Pediatric Hematology/Oncology, Christian Albrechts University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Germany.
Elizabeth K SchweighartPrincess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands.
Shan LinExperimental Hematology and Cancer Biology, Cancer and Blood Disease Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
Mark WunderlichExperimental Hematology and Cancer Biology, Cancer and Blood Disease Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
Janine StutterheimPrincess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands.
Alexander KomkovDmitry Rogachev National Research Center of Pediatric Hematology, Oncology, and Immunology, Moscow, Russia.ORCID 0000-0001-9113-698X
Elena ZerkalenkovaDmitry Rogachev National Research Center of Pediatric Hematology, Oncology, and Immunology, Moscow, Russia.ORCID 0000-0001-9634-5828
Paul EvansHaematological Malignancy Diagnostic Service, St James's University Hospital, Leeds, United Kingdom.
Hesta McNeillWolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
Alex ElderWolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
Natalia Martinez-SoriaWolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
Sarah E FordhamWolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.ORCID 0000-0002-3778-8634
Yuzhe ShiWolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
Lisa J RussellWolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
Deepali PalWolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
Alex SmithEpidemiology and Cancer Statistics Group, University of York, York, United Kingdom.
Zoya KingsburyIllumina Cambridge Ltd., Great Abington, United Kingdom.
Jennifer BecqIllumina Cambridge Ltd., Great Abington, United Kingdom.
Cornelia EckertDepartment of Pediatric Oncology/Hematology, Charité Universitätsmedizin Berlin, Berlin, Germany.
Oskar A HaasSt Anna Children's Cancer Research Institute (CCRI), Vienna, Austria.
Peter CareyDepartment of Paediatric Haematology and Oncology, The Great North Children's Hospital, Newcastle upon Tyne, United Kingdom.
Simon BaileyWolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
Roderick SkinnerWolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.ORCID 0000-0002-1162-675X
Natalia MiakovaDmitry Rogachev National Research Center of Pediatric Hematology, Oncology, and Immunology, Moscow, Russia.
Matthew CollinTranslational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
Venetia BigleyTranslational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.ORCID 0000-0002-3017-2474
Muzlifah HaniffaBiosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
Rolf MarschalekInstitute of Pharmaceutical Biology/DCAL, Goethe-University, Frankfurt/Main, Germany.ORCID 0000-0003-4870-3445
Christine J HarrisonWolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
Catherine A CargoHaematological Malignancy Diagnostic Service, St James's University Hospital, Leeds, United Kingdom.
Denis ScheweDepartment of Pediatrics, Otto von Guericke University Magdeburg, Magdeburg, Germany.
Yulia OlshanskayaDmitry Rogachev National Research Center of Pediatric Hematology, Oncology, and Immunology, Moscow, Russia.ORCID 0000-0002-2352-7716
Michael J ThirmanDepartment of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL.
Peter N CockerillInstitute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.ORCID 0000-0002-4410-8174
James C MulloyExperimental Hematology and Cancer Biology, Cancer and Blood Disease Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
Helen J BlairWolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
Josef VormoorWolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
James M AllanWolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
Constanze BoniferInstitute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.
Olaf HeidenreichWolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.ORCID 0000-0001-5404-6483
Simon BomkenWolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.ORCID 0000-0001-9163-5738
Newcastle University · GBUniversity of Birmingham · GBPrincess Máxima Center · NLDmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology · RUGreat North Children's Hospital · GBCincinnati Children's Hospital Medical Center · USGoethe University Frankfurt · DEIllumina (United Kingdom) · GBSt James's University Hospital · GBBelarusian State University · BYCharité - Universitätsmedizin Berlin · DEChristian-Albrechts-Universität zu Kiel · DENational Health Service · GBOtto-von-Guericke-Universität Magdeburg · DESt Anna Children's Hospital · ATUniversity of Chicago · USUniversity of York · GB
Funding
Instructive role of MLL fusion proteins in lineage determination and leukemogenesisR01CA215504 · NCI · UNIVERSITY OF CHICAGO · PI MULLOY, JAMES C, THIRMAN, MICHAEL J · 2017 to 2021
$3.0MCancer Research UK 12788Cancer Research UK 23389Cancer Research UK 29685Medical Research Council G0802259Medical Research Council MR/S021469/1Medical Research Council MR/S021590/1Medical Research Council MR/W01677X/1National Centre for the Replacement, Refinement and Reduction of Animals in Research NC/P002412/1National Centre for the Replacement, Refinement and Reduction of Animals in Research NC/V001639/1NCI NIH HHS R01 CA215504
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.
Indexed as
Myeloid-Lymphoid Leukemia ProteinPrecursor Cell Lymphoblastic Leukemia-LymphomaChromatinEpigenesis, GeneticGenes, RegulatorHumansOncogene Proteins, FusionChromatinMyeloid-Lymphoid Leukemia ProteinOncogene Proteins, Fusion
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