Highlights from

ASH 2020

62nd Annual Meeting & Exposition of the American Society of Hematology

Virtual 5 - 8 December 2020

Transcriptional and genomic analyses powerful for better understanding ALL subtypes

A large-scale transcriptome and whole genome sequencing analysis identified a new subtype-defining lesion of acute lymphoblastic leukaemia (ALL) as well as a new mechanism of enhancer generation in cancer. Collectively, these data highlight the power of transcriptional and genomic analyses in better understanding the biological relationship among different disease entities.

Acute leukaemia is typically classified based on phenotypic similarities compared to normal haematologic lineages. However, acute leukaemia of ambiguous lineage (ALAL) remains challenging to diagnose, classify, and treat. ALAL includes different forms of leukaemia, that express combinations of myeloid, T-lineage, and stem cell markers, such as acute undifferentiated leukaemia (AUL) and T/myeloid mixed phenotype acute leukaemia (MPAL), as well as early T-cell precursor ALL (ETP-ALL). Although ETP-ALL is seen as a form of T-cell ALL, it shows some similarities with myeloid and stem cell ALL. A single marker, myeloperoxidase (MPO), is often the only distinguishing feature between T/myeloid MPAL and ETP-ALL. However, it is not clear whether phenotypic distinctions accurately capture biological differences among these forms of ALL.

To define the genomic basis of ALAL, Dr Lindsey Montefiori (St. Jude Children's Research Hospital, Tennessee, USA) and colleagues conducted a large transcriptomic and whole genome sequencing analysis of 2,573 primary samples, including cases with T-cell ALL, MPAL, acute myeloid leukaemia (AML), and B-cell ALL. T-distributed stochastic neighbour embedding (t-SNE) and hierarchical clustering analyses of RNA-sequencing data identified a new subtype of 60 samples with a distinct gene expression profile and immunophenotype, categorised across the spectrum of acute leukaemia (45.5% MPAL, 36.4% ETP-ALL, 14.5% AML, 3.6% AUL). These cases exhibited monoallelic expression of BCL11B, which encodes a T-lineage transcription factor that is repressed in haematopoietic stem and progenitor cells (HSPCs), a putative cell of origin for ALAL. As such, BCL11B-deregulating structural variants define a new subtype of ALAL. One of these structural variants, namely a high-copy tandem amplification of a non-coding region (BETA), was observed for the first time and therefore considered a new mechanism of enhancer generation in cancer.

Upon further investigation of 5 HSPC samples using HiChIP, the researchers also showed that rearranged CD34-positive enhancers are active and loop to BCL11B, supporting an enhancer hijacking mechanism.

  1. Montefiori L, et al. Enhancer Hijacking of BCL11B Defines a Subtype of Lineage Ambiguous Acute Leukemia. 62nd ASH Annual Meeting, December 5-8, 2020. Abstract LBA-3.

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