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.
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”.
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.
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.”
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 these hybrid ELP cells that could make 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.”
ENDS
Notes to Editors:
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 mRNA signals reveal 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.
Selected websites:
About Newcastle University
Newcastle University, UK, is a thriving international community of some 27,750 students from over 130 countries worldwide. As a member of the Russell Group of research intensive universities in the UK, Newcastle has a world-class reputation for research excellence in the fields of medicine, science and engineering, social sciences and the humanities. Its academics are sharply focused on responding to the major challenges facing society today. Our research and teaching are world-leading in areas as diverse as health, culture, technology and the environment.
The Research Excellence Framework 2014 (REF) placed Newcastle University 16th in the UK for Research Power and the vast majority of our research (78%) was assessed to be world-leading or internationally excellent. Newcastle University is committed to providing our students with excellent, research-led teaching delivered by dedicated and passionate teachers. This is reaffirmed by achieving the best possible outcome – a Gold Award – in the Teaching Excellence Framework (TEF). https://www.ncl.ac.uk
About Research at Great Ormond Street Hospital
Great Ormond Street Hospital is one of the world’s leading children’s hospitals with the broadest range of dedicated, children’s healthcare specialists under one roof in the UK. The hospital’s pioneering research and treatment gives hope to children from across the UK with the rarest, most complex and often life-threatening conditions. All research at Great Ormond Street Hospital NHS Foundation Trust and UCL Great Ormond Street Institute of Child Health is made possible by the NIHR Great Ormond Street Hospital Biomedical Research Centre.
The Wellcome Sanger Institute
The Wellcome Sanger Institute is a world leading genomics research centre. We undertake large-scale research that forms the foundations of knowledge in biology and medicine. We are open and collaborative; our data, results, tools and technologies are shared across the globe to advance science. Our ambition is vast – we take on projects that are not possible anywhere else. We use the power of genome sequencing to understand and harness the information in DNA. Funded by Wellcome, we have the freedom and support to push the boundaries of genomics. Our findings are used to improve health and to understand life on Earth. Find out more at www.sanger.ac.uk or follow us on Twitter, Facebook, LinkedIn and on our Blog.
About Wellcome
Wellcome supports science to solve the urgent health challenges facing everyone. We support discovery research into life, health and wellbeing, and we’re taking on three worldwide health challenges: mental health, global heating and infectious diseases. https://wellcome.org/
Journal
Nature Medicine
DOI
10.1038/s41591-022-01720-7
Method of Research
Experimental study
Subject of Research
People
Article Title
Single cell mRNA signals reveal a distinct developmental state of KMT2A-rearranged infant B-cell acute lymphoblastic leukemia
Article Publication Date
14-Mar-2022
