New hope for treatment of infant cancer that has puzzled researchers for decades

Date:
March 14, 2022
Source:
Wellcome Trust Sanger Institute
Summary:
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 have now 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.



FULL STORY ==========================================================================
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."

========================================================================== Story Source: Materials provided by Wellcome_Trust_Sanger_Institute. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Eleonora Khabirova and Laura Jardine et al. Single cell mRNA signals
reveal a distinct developmental state of KMT2A-rearranged infant
B-cell acute lymphoblastic leukemia. Nature Medicine, 2022 DOI:
10.1038/s41591- 022-01720-7 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220314120649.htm

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