• HOME
  • NEWS
  • EXPLORE
    • CAREER
      • Companies
      • Jobs
    • EVENTS
    • iGEM
      • News
      • Team
    • PHOTOS
    • VIDEO
    • WIKI
  • BLOG
  • COMMUNITY
    • FACEBOOK
    • INSTAGRAM
    • TWITTER
Saturday, August 2, 2025
BIOENGINEER.ORG
No Result
View All Result
  • Login
  • HOME
  • NEWS
  • EXPLORE
    • CAREER
      • Companies
      • Jobs
        • Lecturer
        • PhD Studentship
        • Postdoc
        • Research Assistant
    • EVENTS
    • iGEM
      • News
      • Team
    • PHOTOS
    • VIDEO
    • WIKI
  • BLOG
  • COMMUNITY
    • FACEBOOK
    • INSTAGRAM
    • TWITTER
  • HOME
  • NEWS
  • EXPLORE
    • CAREER
      • Companies
      • Jobs
        • Lecturer
        • PhD Studentship
        • Postdoc
        • Research Assistant
    • EVENTS
    • iGEM
      • News
      • Team
    • PHOTOS
    • VIDEO
    • WIKI
  • BLOG
  • COMMUNITY
    • FACEBOOK
    • INSTAGRAM
    • TWITTER
No Result
View All Result
Bioengineer.org
No Result
View All Result
Home NEWS Science News Biology

SIRT1 plays key role in chronic myeloid leukemia to aid persistence of leukemic stem cells

Bioengineer by Bioengineer
June 10, 2019
in Biology
Reading Time: 4 mins read
0
Share on FacebookShare on TwitterShare on LinkedinShare on RedditShare on Telegram

Development of effective approaches to target these persistent leukemic stem cells is a challenge for better cancer care

IMAGE

Credit: UAB

BIRMINGHAM, Ala. – Patients with chronic myeloid leukemia can be treated with tyrosine kinase inhibitors. While these effective drugs lead to deep remission and prolonged survival, primitive leukemia stem cells resist elimination during the remission and persist as a major barrier to cure.

As a result, the majority of patients with chronic myeloid leukemia, or CML, require indefinite inhibitor treatment to prevent disease recurrence. They also face risks of noncompliance, toxicity and financial burden. Development of effective therapeutic strategies to improve patient outcomes for CML and related cancers depends on identifying the key mechanisms that contribute to the persistence of these leukemic stem cells.

In a study published in the Journal of Clinical Investigation, Ajay Abraham, Ph.D., Shaowei Qiu, M.D., Ravi Bhatia, M.D., and colleagues at the University of Alabama at Birmingham show how the stress-responsive protein SIRT1 plays important roles in maintaining the regenerative potential of CML leukemic stem cells and promoting leukemia development in CML.

“Our studies provide a conceptual advance and new biological insights regarding the activity of SIRT1 and its role in CML leukemic stem cells,” said senior author Bhatia. At UAB, Bhatia is a professor of medicine, director of the Division of Hematology and Oncology, and interim director of the O’Neal Comprehensive Cancer Center at UAB.

In 2012, Bhatia and colleagues reported that SIRT1 was overexpressed in CML leukemic stem cells compared to normal hematopoietic stem cells, and this overexpression contributed to CML leukemic stem cell maintenance and resistance to tyrosine kinase inhibitors. However, the underlying mechanisms were not known.

To study those mechanisms, the UAB researchers used a CML mouse model that also has a genetic deletion of SIRT1. This allowed them to compare wild-type leukemic stem cells with SIRT1-deletion leukemic stem cells.

Study details

They found that SIRT1 plays an important role to enhance oxidative phosphorylation by the mitochondria in leukemic stem cells. Furthermore, the researchers found that this increased mitochondrial metabolism in leukemic stem cells did not depend on activity of the mutated kinase that transforms the normally quiescent hematopoietic stem cells into leukemic stem cells.

Mitochondria are the powerhouses of the cell, supplying nearly all the energy a cell normally needs. Oxidative phosphorylation uses oxygen in producing energy; non-leukemic hematopoietic stem cells — the non-cancerous blood-forming cells of the body, from healthy mice or humans, produce energy by an alternative metabolism called glycolysis.

Treatment with tyrosine kinase inhibitors is known to suppress leukemic hematopoiesis. When SIRT1-deleted mice were treated with tyrosine kinase inhibitors, the UAB researchers found an even greater suppression of leukemic hematopoiesis.

The SIRT1 knock-out also impaired development of CML in the mouse model. Compared with the CML mice without SIRT1 knock-out, the researchers saw significant delays in developing increased numbers of leukocytes and neutrophils, and delayed enlargement of the spleen and time of death. The deletion also reversed redistribution of CML stem cells from the bone marrow to the spleen.

SIRT1 is a deacetylase enzyme, known to deacetylate and activate the transcriptional co-activator PGC-1-alpha. This enhances mitochondrial DNA replication and gene expression, and it promotes mitochondrial activity. Bhatia and colleagues showed that PGC-1-alpha inhibitors were able to significantly reduce mitochondrial oxygen consumption, a sign of oxidative phosphorylation. Thus, the inhibitors acted similarly to the SIRT1 deletion. This finding supports an important role for PGC-1-alpha in the regulation of mitochondrial metabolism in CML stem and progenitor cells.

The researchers also found that a chemical inhibitor of SIRT1 was able to reduce oxidative phosphorylation in both mouse and human CML leukemic stem cells.

Interestingly, the SIRT1 deletion in normal, non-leukemic blood-forming stem cells did not inhibit steady-state normal hematopoiesis in the mouse model. Bhatia noted that development of effective approaches to target the persistent CML leukemic stem cells that resist tyrosine kinase-inhibitor treatment — while not causing toxicity to normal hematopoietic stem cells — has been a challenge.

Bhatia says the impact of this study extends to other hematological malignancies, including acute myeloid leukemia, myelodysplastic syndromes and myeloproliferative neoplasms.

“Our research reveals new knowledge and concepts regarding the role of SIRT1 in metabolic regulation of hematopoietic stem cell and leukemic stem cell maintenance, growth and resistance,” Bhatia said. “This raises the possibility of developing improved strategies to target kinase-independent metabolic alterations.”

###

Abraham and Qiu are co-first authors on the Journal of Clinical Investigation study, “SIRT1 regulates metabolism and leukemogenic potential in CML stem cells.” Abraham was a postdoctoral fellow in the Division of Hematology and Oncology, UAB Department of Medicine. Qui is a visiting instructor in that division. Besides Abraham, Qiu and Bhatia, co-authors are Balu K. Chacko and Victor M. Darley-Usmar, UAB Department of Pathology, who provided expertise in metabolic analyses; and Hui Li, Andrew Paterson, Jianbo He, Puneet Agarwal, Mansi Shah and Robert Welner, Division of Hematology and Oncology, UAB Department of Medicine.

Support came from National Institutes of Health grant CA95684.

At UAB, Darley-Usmar holds the Endowed Professorship in Mitochondrial Medicine and Pathology.

Media Contact
Jeff Hansen
[email protected]

Original Source

https://www.uab.edu/news/research/item/10534

Tags: cancerCell BiologyDevelopmental/Reproductive BiologyHematologyMedicine/HealthMetabolism/Metabolic Diseases
Share12Tweet8Share2ShareShareShare2

Related Posts

blank

CK2–PRC2 Signal Drives Plant Cold Memory Epigenetics

August 2, 2025
blank

AI-Driven Protein Design Advances T-Cell Immunotherapy Breakthroughs

August 1, 2025

Melanthiaceae Genomes Reveal Giant Genome Evolution Secrets

August 1, 2025

“Shore Wars: New Study Tackles Oyster-Mangrove Conflicts to Boost Coastal Restoration”

August 1, 2025
Please login to join discussion

POPULAR NEWS

  • Blind to the Burn

    Overlooked Dangers: Debunking Common Myths About Skin Cancer Risk in the U.S.

    60 shares
    Share 24 Tweet 15
  • Dr. Miriam Merad Honored with French Knighthood for Groundbreaking Contributions to Science and Medicine

    46 shares
    Share 18 Tweet 12
  • Neuropsychiatric Risks Linked to COVID-19 Revealed

    41 shares
    Share 16 Tweet 10
  • Study Reveals Beta-HPV Directly Causes Skin Cancer in Immunocompromised Individuals

    38 shares
    Share 15 Tweet 10

About

We bring you the latest biotechnology news from best research centers and universities around the world. Check our website.

Follow us

Recent News

AI Virtual Lab Engineers New SARS-CoV-2 Nanobodies

GBA1 Variants’ Impact on Parkinson’s: In Silico Analysis

Rotterdam Oncology: Premier Head & Neck Biobank

  • Contact Us

Bioengineer.org © Copyright 2023 All Rights Reserved.

Welcome Back!

Login to your account below

Forgotten Password?

Retrieve your password

Please enter your username or email address to reset your password.

Log In
No Result
View All Result
  • Homepages
    • Home Page 1
    • Home Page 2
  • News
  • National
  • Business
  • Health
  • Lifestyle
  • Science

Bioengineer.org © Copyright 2023 All Rights Reserved.