Klin Padiatr 2022; 234(03): 190
DOI: 10.1055/s-0042-1748750
Abstracts

Epigenetic modifiers direct lineage switch in MLL-AF4 leukemia

K Szoltysek
1   Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands
,
R Tirtakusuma
2   Wolfson Childhood Cancer Research Centre, Centre for Cancer, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK,
,
M Ashtiani
1   Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands
,
S Nakjang
2   Wolfson Childhood Cancer Research Centre, Centre for Cancer, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK,
,
V V Grinev
3   Department of Genetics, the Faculty of Biology, Belarusian State University, 220030 Minsk, Republic of Belarus
,
J Hehir-Kwa
1   Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands
,
EK Schweighart
1   Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands
,
S Bomken
2   Wolfson Childhood Cancer Research Centre, Centre for Cancer, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK,
,
O Heidenreich
1   Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands
2   Wolfson Childhood Cancer Research Centre, Centre for Cancer, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK,
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MLLr initiates onset of high-risk leukemia which lineage – ALL or AML – is determined by the MLL-fusion partner. MLL-AF4 pre-dominantly associates with B-ALL, however ~1% of cases convert from CD19+ lymphoid into CD19neg myeloid phenotype.

Here we aimed to identify molecular basis of lineage switching in a cohort of MLL-AF4 acute leukemia patients undergoing myeloid relapses. Performed genomic and transcriptomic studies revealed low mutational load and substantial changes in transcriptomic pattern observed at AML relapse. We found CHD4 gene, a core component of chromatin remodeling NuRD complex, to be disrupted in analyzed cases, pointing into its crucial function in maintenance of lymphoid commitment decisions.

Comparison with non-lineage switching MLL-AF4 patients showed hyperactivation of translational processes and co-existence of two signatures at B-ALL stage of our patients: B-cell and multi-potent, progenitor-like. This data suggests that enhanced cellular plasticity may facilitate CD19 loss and myeloid differentiation, directed by dysfunctional epigenetic modifiers, leading to treatment escape route to e.g. epitope-directed immunotherapies.



Publication History

Article published online:
17 May 2022

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