Navigation Links
New research uncovers diverse metabolic roles for PML tumor suppressor gene
Date:8/30/2012

BOSTON -- Two papers led by scientific teams from the Cancer Genetics Program at Beth Israel Deaconess Medical Center (BIDMC) shed new light on the genetic mechanisms underlying cellular energy and metabolism and, at the same time, highlight both the challenges and opportunities of genetic approaches to cancer treatment.

Appearing in the September 2012 issues of The Journal of Clinical Investigation (JCI) and Nature Medicine, the new findings reveal surprising insights into how PML regulates metabolism via the fatty acid oxidation (FAO) pathway and, in the process, uncover paradoxical roles for this tumor suppressor gene.

"The real story lies in the juxtaposition of these two papers, the way they jointly illuminate the braided function of PML in the FAO pathway," says the papers' senior author Pier Paolo Pandolfi, MD, PhD, Director of Cancer Genetics at BIDMC and George C. Reisman Professor of Medicine at Harvard Medical School. The Pandolfi laboratory has been studying the PML (promyelocytic leukemia protein) tumor suppressor gene, for more than 20 years.

Fatty-acid oxidation is the fat-burning metabolic process that is of importance to the energy of all cells. The two studies examined the impact of the FAO process in different biomedical situations including obesity, breast cancer and hematopoetic stem cell maintenance. Importantly, both publications determined that the FAO pathway could be a target for pharmacologic treatments.

The JCI paper defines the mechanism by which PML regulates FAO (involving the regulation of peroxisome proliferator-activated receptors or PPARs). According to first author Arkaitz Carracedo, PhD, a former postdoctoral fellow in the Pandolfi laboratory and currently Ikerbasque Research Professor at the research institute CIC bioGUNE, Bizkaia, Spain, the findings demonstrate that alterations in this pathway result in excessive fat accumulation and obesity in genetically engineered mouse models. In other words, when PML is highly expressed, cellular metabolism is enhanced and the mice were able to briskly burn fat and avoid gaining weight. Conversely, when PML was lost, the animals grew obese.

But, the team also made the paradoxical discovery that PML's enhanced cellular metabolism appeared to provide breast cancer cells with the energy needed to survive. These findings are further supported by data showing PML is highly expressed in a subset of breast cancers with poor prognosis, notes Carracedo. Instead of maintaining its function as a tumor suppressor and keeping breast cancer cells under control, PML is providing breast cancer with a survival advantage. These findings aligned with work by other labs that have found a relationship between high PML expression and breast cancers with poor prognosis.

In the second paper, in the September 2012 issue of Nature Medicine, Keisuke Ito, MD PhD, together with co-lead author Arkaitz Carracedo, looked at PML's role in regulating hematopoetic stem cells (HSCs), again through the FAO pathway, and defined for the first time the contribution of lipid metabolism to maintaining the function of HSCs.

HSCs replenish blood cells throughout the lifespan of an organism, and so they are critical to the aging process, explains Ito, also a former postdoctoral fellow in the Pandolfi laboratory and currently a member of the faculty at the Albert Einstein College of Medicine. The authors discovered that inhibition of fatty acid oxidation could represent an effective therapy for leukemia, as well as other forms of cancer but that it simultaneously posed a risk to the replenishment of HSCs. "Our results uncover a crucial metabolic requirement involving PPAR-delta signaling and FAO for preservation of the delicate equilibrium between HSC maintenance and function," the authors write. The findings have straightforward therapeutic implications for the improvement of both the efficacy of bone marrow transplantation (BMT) and the treatment of hematological malignancies.

"These two studies highlight both the opportunities and complexities of genetic approaches to human disease," notes Pandolfi. "Our next logical step will be to identify a potential path for therapeutic intervention through the opposing Scylla and Charybdis-like threats and benefits of this pathway," he says, referring to the two sea monsters that sailors of mythology had to navigate. "Through pharmacological dosage and scheduling, we will come up with a way to reap the benefits of PML and FAO regulation, while reducing or even eliminating its risks. The opportunity is there since we have drugs that can modulate both PML levels and FAO, and we have begun testing these concepts right away in our 'mouse hospital.'"


'/>"/>

Contact: Bonnie Prescott
bprescot@bidmc.harvard.edu
617-667-7306
Beth Israel Deaconess Medical Center
Source:Eurekalert

Related medicine news :

1. UCLA Brain Injury Research Center gets NCAA funding for research on sports concussions
2. NIH awards $20 million over 5 years to train next generation of global health researchers
3. Researchers develop a new cell and animal model of inflammatory breast cancer
4. Researchers uncover a viable way for colorectal cancer patients to overcome drug resistance
5. Sexually abused boys at risk for more unsafe sex: UBC research
6. Researchers Find Gene Mutations That May Be a Key to Autism
7. LSUHSC research finds HPV-related head & neck cancers rising, highest in middle-aged white men
8. Researchers find evidence of banned antibiotics in poultry products
9. Presidential keynote address and new research highlights from the American Society of Pediatric Otolaryngology meeting
10. Scientific session and new research highlights
11. NJ stroke researchers report advances in spatial neglect research at AAN Conference
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:10/13/2017)... , ... October 13, 2017 , ... The Visiting Nurse ... Market. Featuring a collection of specialty vendors and unique items from across the nation, ... quality-focused health and wellness services offered by the VNA. The boutique will be ...
(Date:10/13/2017)... VA (PRWEB) , ... October 13, 2017 , ... ... of DevOps and Agile Software Development, has been awarded a contract by the ... Blanket Purchase Agreement (BPA) aims to accelerate the enterprise use of Agile methodologies ...
(Date:10/12/2017)... New Orleans, LA (PRWEB) , ... October 12, 2017 , ... ... fitness centers in the U.S., announced today its plans to open a flagship location ... club will occupy the former Rooms To Go store next to Office Depot in ...
(Date:10/12/2017)... , ... October 12, 2017 , ... ... delivery system that we intend to develop to enable prevention of a major ... to severe hearing loss, especially in pediatric patients. For cisplatin, hearing loss is ...
(Date:10/12/2017)... (PRWEB) , ... October 12, 2017 , ... ... been named one of Michigan’s 2017 Best and Brightest in Wellness® by Best ... in Wellness® awards program on Friday, Oct. 20 from 7:30 a.m. to 2 ...
Breaking Medicine News(10 mins):
(Date:10/11/2017)... , Oct. 11, 2017  BioPharmX Corporation (NYSE MKT: ... that developed an innovative way to use nonlinear optical ... delivery of new drugs. ... Dermatology Conference will show how researchers from BioPharmX and ... Medical School used a suite of imaging techniques in ...
(Date:10/11/2017)... 11, 2017  True Health, a leader in ... effort during National Breast Cancer Awareness month to ... Research recently ... that more than 10 million American women are ... BRCA1 or BRCA2 and have not had testing. These ...
(Date:10/10/2017)... -- NDS received FDA 510(k) clearance in May 2017 for its highly ... designed for endoscopy environments. An innovative secondary monitor solution, ZeroWire ... support the improvement of patient outcomes, procedural efficiency, and the lowering ... ... ...
Breaking Medicine Technology: