18 March 2022

UK scientists have uncovered one possible reason why a type of leukaemia in infants is often more severe than in older children, unlocking hopes for new treatments.

Subtle differences in the cell type that causes B acute lymphoblastic leukaemia (B-ALL) could be behind this difference, say the scientists from the Wellcome Sanger Institute in Cambridge, Great Ormond Street Hospital in London, Newcastle University and collaborators.

The study, published Nature Medicine, examined infant B-ALL cases caused by rearrangements in the KMT2A gene. The team found some promising drug targets that could eventually lead to effective treatments for infant B-ALL.

Although most cases of B-ALL in children are curable, the success rate of treatment in infants under one year of age is under 50%, the researchers say.

In this study, researchers looked at KMT2A-rearranged infant B-ALL by comparing cancer cells to normal human blood cells.

They examined gene expression data from 1,665 childhood leukaemia cases and single-cell mRNA data from about 60,000 normal foetal bone marrow cells. The team found that infant B-ALL exhibited distinct cellular signals with significant contribution from early lymphocyte precursors (ELPs).

Dr Laura Jardine from Newcastle University, co-first author with Dr Eleonora Khabirova of the Wellcome Sanger Institute, said: “Leukaemias are usually classified by the cell type involved, and in the case of B acute lymphoblastic leukaemia (B-ALL) we talk about B cell progenitors. But our analysis of this disease has shown that this is actually an early lymphocyte precursor leukaemia.”

As well as distinguishing ELP cells from other types of B cell, the researchers found that the closer an ELP cell was to becoming a mature B cell, the better the outcome for the patient.

Joint senior study author Dr Jack Bartram, from Great Ormond Street Hospital, said: “As part of this study, we think that we have unpicked why B acute lymphoblastic leukaemia (B-ALL) is more responsive to treatment in some children, but why it’s not so successful for infants.

 “Cancers with more ‘mature’ early lymphocyte precursors (ELPs) have characteristics that seem to respond better to treatment. These more mature cells are more common in B-ALL in older children but sadly not for our younger patients, meaning the treatment is less effective.

“The challenge now is to develop our understanding and confirm these suspicions so that we can improve treatments for all patients.”

When the team went on to investigate the molecular landscape of KMT2A-rearranged infant B-ALL, they found that unlike normal ELP cells, those involved in cancer had molecular features of different cell types.

This, they say, suggests a malfunction in the normal process of differentiation.

The team identified multiple biological pathways and markers in the hybrid ELP cells that could make promising targets for new therapies.

Wellcome Sanger Institute’s Dr Sam Behjati, a joint senior author of the study, said: “Although it is too soon to draw definitive conclusions about why B-ALL outcomes are poorer in infants compared to older children, the study offers compelling evidence that the maturity of the cells involved is a key factor.

“As well as generating new drug targets, these data will allow us to observe how the ‘cell type’ of certain cancers corresponds to patient outcomes, allowing us to better assess disease severity and determine the best course of treatment.”

Source: Khabirova E, Jardine L, Coorens THH, Webb S, Treger TD, Engelbert J, Porter T, Prigmore E, Collord G, Piapi A, Teichmann SA, Inglott S, Williams O, Heidenreich O, Young MD, Straathof K, Bomken S, Bartram J, Haniffa M & Behjati S (2022). “Single cell mRNA signals reveal a distinct developmental state of KMT2A-rearranged infant B-cell acute lymphoblastic leukemia.” Nature Medicine, doi: 10.1038/s41591-022-01720-7  

Link: https://www.nature.com/articles/s41591-022-01720-7

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