New hope for treatment of infant cancer that has puzzled researchers for decades
New research has begun to unravel the mystery of why a particular form of leukaemia in infants has defied efforts to improve outcomes, despite significant improvements in treating older children. Scientists from the Wellcome Sanger Institute, Great Ormond Street Hospital, Newcastle University and their collaborators found subtle differences in the cell type that causes B acute lymphoblastic leukaemia (B-ALL) that may help to explain why some cases are more severe than others.
The study, published today (14 March 2022) in Nature Medicine, focused on the majority of infant B-ALL cases caused by changes to the KMT2A gene. The findings provide a number of promising drug targets, raising hopes that effective treatments for infant B-ALL may be developed in the future.
Acute lymphoblastic leukaemia (ALL) can take various forms, depending on the cell type involved. These cancers occur when cells malfunction as they develop from haematopoietic stem cells to mature blood cells. In the case of B-ALL, disease arises from a type of immune cell called B lymphocytes, more commonly known as B cells.
B-ALL in children was once a universally fatal disease that is now curable in the majority of cases1. An exception is B-ALL in children below one year of age, where treatment is successful in less than 50 per cent of cases, with no significant improvement in the last two decades. Treatments that are proven in tackling other forms of leukaemia, such as bone marrow transplants, have proved ineffective against infant B-ALL. It is currently treated with strong chemotherapy, which can be hard for the patient to endure even if they are cured.
In this paper, researchers set out to study KMT2A-rearranged infant B-ALL by comparing cancer cells to normal human blood cells. Gene expression data from 1,665 childhood leukaemia cases was referenced against single-cell mRNA data from around 60,000 normal fetal bone marrow cells2.
Analysis found that infant B-ALL exhibited distinct cellular signals with a notable contribution from early lymphocyte precursors (ELPs)3, an immature immune cell type that normally develops into B cells.
“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.”
Dr Laura Jardine, a first author of the study from Newcastle University
As well as being able to distinguish 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.
“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.”
Dr Jack Bartram, a senior author of the study from Great Ormond Street Hospital
To further investigate the molecular landscape of KMT2A-rearranged infant B-ALL, researchers compared gene expression profiles of the cancer to that of normal ELP cells. Unlike normal ELP cells, those involved in cancer had molecular features of different cell types, suggesting a malfunction in the normal process of differentiation. Multiple biological pathways and markers were identified in this hybrid ELP cells that could make promising targets for new therapies.
“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.”
Dr Sam Behjati, a senior author of the study from the Wellcome Sanger Institute
More information
1 For more information on acute lymphoblastic leukaemias and how the normal development of blood cells can go wrong, see the Cancer Research UK website.
2 Single-cell mRNA data was generated by the Human Cell Atlas (HCA) project, an international collaborative consortium which is creating comprehensive reference maps of all human cells as a basis for understanding human health and for diagnosing, monitoring, and treating disease. https://www.humancellatlas.org
3 ELPs are a type of lymphoid cell that retain the ability to differentiate into other types of lymphocytes. ELPs also retain some capacity to differentiate into bone marrow cells.
Publication:
Eleonora Khabirova and Laura Jardine et al. (2022). Single-cell transcriptomics reveals a distinct developmental state of KMT2A-rearranged infant B-cell acute lymphoblastic leukemia. Nature Medicine. DOI: https://doi.org/10.1038/s41591-022-01720-7
Funding:
This research was funded by Wellcome, the Lister Institute of Preventative Medicine, Newcastle NIHR-Biomedical Research Centre, the National Institute for Health Research, the Medical Research Council and Cancer Research UK.
