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 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.

Identification of IKZF1 genetic mutations as new molecular subtypes in acute myeloid leukaemia

“…Conversely, RUNX1T1 , a well‐known factor for haematopoietic differentiation and myeloid development, was highly expressed in IKZF1 N159S knock‐in AML cells instead of IKZF1 N159Y 47 . These data suggested that the dysregulation of gene transcriptional profiles may underpin the fundamental lineage reprogramming 45 . We therefore propose that different regulation effect of genetic mutations at the same amino acid site of transcription factors may lead to different regulation effect and leukaemia lineage.…”

“…Only a few studies have reported the rare IKZF1 mutations in acute myeloid leukaemia with a low frequency 26,43 . On the other hand, the lineage plasticity refers to the ability of transition from one committed developmental pathway to another, 44 relapse can be associated with a lineage switch from acute lymphoblastic to acute myeloid leukaemia, which may be resistant to chemo‐ and immunotherapies and result in poor clinical outcomes 45 . Previous studies have shown that the lineage switching is linked to a major rewiring of gene regulatory networks in patients with KMT2A translocations 34,44,45 .…”

The EGR3 regulome of infant KMT2A-r acute lymphoblastic leukemia identifies differential expression of B-lineage genes predictive for outcome

“…Importantly, CD19-directed therapies including CAR T cells and Blinatumomab were reported to lead to lineage switch of infant KMT2A :: AFF1 ALL [ 44 – 46 ]. This process has been shown to be accompanied by a loss of the B-lineage-specific transcription factors EBF1 and PAX5 [ 47 ]. As our data suggest a collaborative effect between PAX5 and EGR3, the role of EGR3 during lineage switch of KMT2A -r B ALL needs further investigation.…”

Non-canonical D1-D2 recombination produces two types of rearrangements and represents a conservative hidden stage of T-cell receptor beta chain generation

“…For now, we do not completely understand how it affects T cell immunity in health and disease. However, we believe this new type of rearrangements is significant for both basic knowledge and applied research as a novel marker for clonality analysis [18,19] and minimal residual disease monitoring [20,21] in lymphoid malignancies.…”