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Sanger Institute helps unravel mystery of why type of childhood leukaemia is much harder to treat in those under age of one

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The mystery of why a type of leukaemia that can now be cured in most children has proved much harder to treat in infants under one year old is being unravelled by scientists.

Researchers at the Wellcome Sanger Institute, Great Ormond Street Hospital, Newcastle University and their collaborators found that there are subtle differences in the cell type that causes B acute lymphoblastic leukaemia (B-ALL).

Sam Behjati at the Wellcome Sanger Institute
Sam Behjati at the Wellcome Sanger Institute

Once universally fatal, there has been considerable progress made in its treatment. But treatment remains successful in less than 50 per cent of cases in children under the age of one, with no significant improvement in the last two decades.

Treatments proven to work in other forms of the disease, such as bone marrow transplants have been ineffective against infant B-ALL, which is currently treated with strong chemotherapy. This can be hard for the patient to endure.

Acute lymphoblastic leukaemia (ALL) takes various forms, depending on the cell type involved, but occurs when cells malfunction while developing from haematopoietic stem cells to mature blood cells.

In B-ALL, a type of immune cell called B lymphocytes - or B cells - are involved, and the study focused on the majority of cases, in which changes are seen in the KMT2A gene.

Gene expression data from 1,665 childhood leukaemia cases was compared by the team against single-cell mRNA data from around 60,000 normal fetal bone marrow cells.

They found distinct cellular signals in infant B-ALL, with a notable contribution from early lymphocyte precursors (ELPs). This is an immature immune cell type that normally develops into B cells.

Dr Laura Jardine, a first author of the study from Newcastle University, 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.”

The closer an ELP cell was to becoming a mature B cell, the better the outcome proved for the patient.

Dr Jack Bartram, a senior author of the study 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.”

Exploring the molecular landscape of KMT2A-rearranged infant B-ALL further, the researchers then compared gene expression profiles of the cancer to that of normal ELP cells, finding they had molecular features of different cell types.

This suggested there had been a malfunction in the normal process of differentiation.

There were multiple biological pathways and markers identified in these hybrid ELP cells that could prove to be promising targets for new therapies.

Dr Sam Behjati, a senior author of the study from the Wellcome Sanger Institute, said: “Though it is too early to draw definitive conclusions about why B acute lymphoblastic leukaemia (B-ALL) has much poorer outcomes in infants than in older children, this 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.”

The work was published on Monday (March 14) in Nature Medicine.

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