Mouse study may help doctors choose treatments for leukemia patients


Date:
February 23, 2022
Source:
University of Wisconsin-Madison
Summary:
Some genetic mutations linked to leukemia are less than useful
guides to making treatment decisions for patients. A new study
suggests a group of clinical signs that can be paired with genetic
testing to better inform the timing of more aggressive treatment.



FULL STORY ==========================================================================
Some genetic mutations linked to leukemia are less than useful guides to
making treatment decisions for patients. A new study from the University
of Wisconsin- Madison suggests a group of clinical signs that can
be paired with genetic testing to better inform the timing of more
aggressive treatment.


========================================================================== Studies of leukemia, which is cancer of the blood and blood-forming
cells, have revealed alterations in genes that can be associated with
the disease, and these genetic changes can be passed from one generation
to the next. In certain cases, these alterations give doctors a way to
gauge disease risk. For others, the consequences remain obscure. Even when
the link between a particular genetic red flag and disease is strong, it
may be difficult to pinpoint when serious stages of the disease may begin.

"That can be extremely variable. In a family that shares a common
mutation, a grandfather might not present with symptoms until leukemia
abruptly emerges," says UW-Madison cancer researcher Alexandra Soukup. "By contrast, one of their grandchildren with the same genetic alteration
may have serious symptoms starting at age seven -- like lymphedema, which
is severe swelling in the arms and legs, or low blood cell levels called cytopenia, which can cause life- threatening infections. We want to know
what environmental and genetic factors trigger the disease presentation." Clinicians treating patients with genetic mutations likely to cause
leukemia would like to know as well, because their options range from light-handed monitoring or drugs to invasive procedures including
radiation, chemotherapy and stem cell transplants.

"Right now, the gold standard for treatment is a bone marrow transplant," Soukup says. "But those occur when there's already relatively severe
disease presence, elderly patients are often not eligible for a
transplant, and there can be life-threatening reactions to transplants."
The complications of leukemia, which causes the bone marrow to make too
few blood cells or abnormal blood cells, can be triggered by exposure
to a pathogen or toxin, requiring the body to ramp up production of new
blood cells.



========================================================================== Soukup, a UW-Madison Cell & Regenerative Biology professor, and Emery
Bresnick, director of the Wisconsin Blood Cancer Research Institute, and collaborators exposed mice harboring a genetic mutation associated with leukemia to "triggers" that created a model for bone marrow failure. This
often precedes the development of leukemia. The researchers published
their findings recently in the journal Science Advances.

"These mutations have little to no impact on the steady-state production
of blood cells, and the mice containing the mutation might seem normal
most of the time," says Soukup, a scientist in Bresnick's lab. "It's
just when you expose them to other stresses that severe defects emerge."
The researchers stressed the mice in one of three ways, to mimic in
a short time the sort of environmental and immunological challenges
humans may face over longer terms -- with a common chemotherapy drug,
a component in bacterial cell walls that causes inflammation, or a drug
used to ramp up stem cell division before human transplants. They wanted
to see how the mice's bone marrow would respond. In healthy marrow,
stem cells should divide and mature into new blood cell producers to
pick up the slack in times of trouble.

"In all of our cases, the stem cells seemed relatively normal, but
they failed to respond or were extremely impaired in their response to
expand," Soukup says. "With the chemotherapeutic, you'd expect the stem
cells to expand greatly and blood cells to regenerate, replacing what
was destroyed by the chemotherapy. My mutant animals failed to mount
a response." Without the stem cell expansion, the animals were overcome
by bone marrow failure.

By exploring the ways in which the mutant mice responded to these
stressors, the researchers can understand the sorts of human health issues
-- like recurring infections -- that may bring on a life-threatening
leukemia.

"Our mouse model provides a unique system to discover what may trigger
severe disease presentations in humans, and we can use this system to
develop strategies to counteract or nullify the triggering. We would
want to apply such strategies to patients," Soukup says. "If you've
already presented with X, Y and Z, and you've been exposed to these risk factors, this may enable medical decisions to avoid the crisis scenario
in which severe disease rapidly emerges." This research was supported
by grants from the National Institutes of Health (DK68634, T32 HL07899, P30CA014520, 1S10RR025483-01) and Scholar Awards to Dr.

Soukup from the Leukemia & Lymphoma Society and American Society of
Hematology.

========================================================================== Story Source: Materials provided
by University_of_Wisconsin-Madison. Original written by Chris
Barncard. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Alexandra A. Soukup, Daniel R. Matson, Peng Liu, Kirby D. Johnson,
Emery
H. Bresnick. Conditionally pathogenic genetic variants of a
hematopoietic disease-suppressing enhancer. Science Advances,
2021; 7 (50) DOI: 10.1126/sciadv.abk3521 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220223104941.htm

--- up 11 weeks, 4 days, 7 hours, 13 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)