Bone marrow cancer: Potential drug targets
Date:
March 17, 2022
Source:
Mayo Clinic
Summary:
New research finds that patients with ASXL1-mutant chronic
myelomonocytic leukemia -- an uncommon type of cancer of the bone
marrow -- have distinctive epigenetic changes that can activate
harmful genes and cause the cancer to grow faster. The ASXL1 genetic
mutation also can transform the disease into the more aggressive
acute myeloid leukemia.
FULL STORY ==========================================================================
New research from Mayo Clinic's Center for Individualized Medicine
finds that patients with ASXL1-mutant chronic myelomonocytic leukemia
-- an uncommon type of cancer of the bone marrow -- have distinctive
epigenetic changes that can activate harmful genes and cause the cancer
to grow faster. The ASXL1 genetic mutation also can transform the disease
into the more aggressive acute myeloid leukemia.
==========================================================================
The study, published in Nature Communications, helps to clarify a
potential therapeutic strategy and adds to the knowledge of ASXL1 gene expression.
Epigenetics refers to chemical modifications of a cell's genetic material
that control how genes are expressed and affect the interpretation of
the DNA code.
Research shows epigenetics play a critical role in the development and progression of many diseases, including cancer.
"The epigenome in patients with these ASXL1 gene mutations is changed in a
way that allows the cancer cells to switch on genes that are detrimental
to the patients," says Moritz Binder M.D., a Mayo Clinic hematologist
and scientist, and the lead author of the study. Dr. Binder is a 2021
Gerstner Family Career Development awardee.
"These epigenetic changes don't affect the DNA blueprint itself,"
Dr. Binder explains. "It affects how to the blueprint is read -- which
pages to read and which pages not to read." Chronic myelomonocytic
leukemia is a cancer that typically affects people 60 and older. It starts
in blood-forming cells of the bone marrow and invades the blood. Nearly
40% of patients with chronic myelomonocytic leukemia have a mutation in
the ASXL1 gene.
========================================================================== "Unfortunately, patients with ASXL1 mutations do not fare well and do not respond as well to the treatments currently available," Dr. Binder says.
For the study, Dr. Binder and his team conducted a comprehensive
multi-omics interrogation using a variety of high-throughput sequencing methods. Multi- omics offers the opportunity to understand the flow of information that underlies disease.
The researchers compared samples from patients with and without ASXL1
mutations and analyzed the activity of genes along with molecules
around the DNA. The investigation included gene expression and several modifications affecting the packaging of the DNA.
"This allowed us to perform modeling to draw inference about the effect
of epigenetic changes in isolation and in concert on leukemogenic gene expression in ASXL1-mutant chronic myelomonocytic leukemia," Dr. Binder
says.
Overall, they found that ASXL1 mutations are associated with the
overexpression of key genes that drive leukemia.
"Our study supports the notion that several important leukemogenic
driver genes are under the control of regulatory elements in the genome,"
Dr. Binder says.
The data suggest that these regulatory elements are only functional
in patients with ASXL1-mutant chronic myelomonocytic leukemia and may
therefore represent new individualized therapeutic targets. Dr. Binder
is planning to translate these findings into early phase clinical
trials soon.
"Our study is the basis for ongoing work to further explore ways to target these patient-specific regulatory elements with novel small-molecule
drugs, "Dr. Binder says. "With this approach, we hope to restore normal
gene expression, or at least treat the cancer cells in a new way to
overcome the detrimental effect of ASXL1 mutations."
========================================================================== Story Source: Materials provided by Mayo_Clinic. Original written by
Susan Murphy. Note: Content may be edited for style and length.
========================================================================== Journal Reference:
1. Moritz Binder, Ryan M. Carr, Terra L. Lasho, Christy M. Finke,
Abhishek
A. Mangaonkar, Christopher L. Pin, Kurt R. Berger, Amelia
Mazzone, Sandeep Potluri, Tamas Ordog, Keith D. Robertson, David
L. Marks, Martin E. Fernandez-Zapico, Alexandre Gaspar-Maia,
Mrinal M. Patnaik. Oncogenic gene expression and epigenetic
remodeling of cis-regulatory elements in ASXL1-mutant chronic
myelomonocytic leukemia. Nature Communications, 2022; 13 (1) DOI:
10.1038/s41467-022-29142-6 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/03/220317172451.htm
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