Researchers uncover evolutionary forces at play in the aging of the
blood system and identify people at increased risk of blood cancer

Date:
August 17, 2021
Source:
Ontario Institute for Cancer Research
Summary:
Study shows how the interplay of positive, neutral and negative
evolutionary selection acting on mutations in aging blood stem
cells can lead to acute myeloid leukemia (AML) in some individuals
with age-related clonal hematopoiesis (ARCH).



FULL STORY ==========================================================================
As people age, mutations can build up in blood stem cells and their clones
in a process known as age-related clonal hematopoiesis, or ARCH. ARCH
can be a risk factor for acute myeloid leukemia (AML), a form of blood
cancer. New research provides insight into why some with ARCH go on to
develop AML and others don't.

These findings, recently published in Nature Communications,have the
potential to significantly advance the early detection and treatment
of AML by identifying those at high risk of the disease so they can be monitored more closely.


==========================================================================
The study, co-led by Dr. Philip Awadalla, Senior Principal Investigator
and Director, Computational Biology at the Ontario Institute for Cancer Research (OICR) and Dr. Quaid Morris, Member, Computational and Systems Biology, Memorial Sloan Kettering Cancer Center (MSK) and OICR Associate,
shows how the interplay of positive, neutral and negative evolutionary selection acting on mutations in aging blood stem cells can lead to AML
in some individuals with ARCH. They did so by illustrating how negative selection, or 'purifying selection', present in individuals who did not
go on to develop a malignancy, prevents disease-related cells from coming
to dominate the cell population.

These discoveries allow for the differentiation between those with ARCH
who are at increased risk of developing AML and those who are not.

"We have shown that the constellation of evolutionary forces at play
within hematopoietic stem cells can be a robust indicator of those who are
at increased risk of blood cancers such as AML," says Awadalla. "Being
able to accurately classify patients based on risk can allow for more
frequent and intensive screening for those with ARCH mutations with a concerning evolutionary signature." The research team computationally generated more than five million blood populations, trained a deep
neural network model (a type of machine learning) to recognize different evolutionary dynamics and employed the model to analyze blood samples
that had undergone deep genomic sequencing. These samples were from 92 individuals who went on to develop AML, and 385 who did not despite the presence of ARCH. The study is one of the first to use a single system
of tools to capture the interaction of the multiple evolutionary forces
at play in ARCH.

"The models we developed in this study can significantly increase the
value of ARCH as a biomarker for blood malignancies," says Morris. "Our
team is looking forward to continuing to bolster our understanding of
ARCH and seeing these advancements help patients." The researchers were
able to show that these alternative evolutionary models were predictive
of AML risk over time. Similarly, these tools were able to identify
genes where mutations that are damaging to stem cells can accumulate.

"Our novel application of deep learning tools and population genetic
models to genomic sequencing allowed us to classify the evolutionary interactions within a blood sample with a very high degree of accuracy,"
says Kimberly Skead, first author and PhD Candidate in the Awadalla
and Morris Labs at OICR, the Department of Molecular Genetics at
the University of Toronto and the Vector Institute for Artificial
Intelligence. "This level of resolution enabled us to understand how
both positive and negative selection shape the aging blood system and to establish strong links to individual health outcomes, which bodes well
for potential clinical use." "In the future, we can anticipate screening
blood samples for early detection of disease and blood cancers. With these tools we can more proactively monitor people's health. Early detection
of cancer is critical with respect to prevention and effectiveness of treatment," adds Awadalla.

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


========================================================================== Journal Reference:
1. Kimberly Skead, Armande Ang Houle, Sagi Abelson, Mawusse Agbessi,
Vanessa
Bruat, Boxi Lin, David Soave, Liran Shlush, Stephen Wright, John
Dick, Quaid Morris, Philip Awadalla. Interacting evolutionary
pressures drive mutation dynamics and health outcomes
in aging blood. Nature Communications, 2021; 12 (1) DOI:
10.1038/s41467-021-25172-8 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210817094151.htm

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