Nav: Home

Single gene cluster loss may contribute to initiation/progression of multiple myeloma

February 20, 2020

Bottom Line: The loss of one copy of the miR15a/miR16-1 gene cluster promoted initiation and progression of multiple myeloma in mice.

Journal in Which the Study was Published: Published online in Blood Cancer Discovery, the latest journal of the American Association for Cancer Research

Author: Marta Chesi, PhD, associate professor of medicine at the Mayo Clinic

Background: Multiple myeloma is a cancer of antibody-producing cells called plasma cells. It is preceded by a premalignant condition known as monoclonal gammopathy of undetermined significance (MGUS), in which abnormal plasma cells are present but do not expand. A hallmark of both MGUS and multiple myeloma is the detection of an M spike, which indicates the accumulation of an abnormal secreted antibody in the patient's blood.

"The risk of progression from MGUS to malignant multiple myeloma is approximately 1 percent each year, but the factors that contribute to progression are not well understood," said Chesi. "The purpose of our study was to model genetic risk factors that may contribute to initiation and progression of multiple myeloma. This understanding could eventually allow us to identify the mechanisms that increase the risk of progressing to multiple myeloma."

One copy of chromosome 13 is deleted in approximately half of patients with MGUS and multiple myeloma; however, the significance of this deletion on prognosis and disease progression remains controversial. Chesi and colleagues hypothesized that individual genes on chromosome 13 may promote disease initiation and/or progression.

The authors examined the impact of two genetic loci found on human chromosome 13 - RB1 and MIR15A/MIR16-1 - on disease initiation and progression. Both RB1 and MIR15A/MIR16-1 are considered tumor suppressor genes due to their roles in regulating cellular proliferation. The RB1 protein is known to be inactivated in many cancers, including multiple myeloma. A previous study demonstrated that deletion of MIR15A/MIR16-1 enhances proliferation of human B cells, and deletion of the gene in mice promotes development of another blood cancer, chronic lymphocytic leukemia.

How the Study was Conducted and Results: In this study, the authors deleted a single copy of either Rb1 or miR15a/miR16-1 in wild-type mice and in a transgenic mouse model of multiple myeloma they previously developed. The authors found that deletion of one copy of Rb1 did not affect disease initiation or progression. In contrast, deleting one copy of miR15a/miR16-1 in wild-type mice significantly accelerated the development of an M-spike. Furthermore, the deletion of one copy of miR15a/miR16-1 in mice with multiple myeloma significantly enhanced the aggressiveness of the disease and led to increased expression of genes that promote cellular proliferation.

The authors also analyzed a genetic dataset of multiple myeloma patients and found that deletion of one copy of MIR15A/MIR16-1 in patient tumors was associated with increased expression of the same cellular proliferation genes that were upregulated in mice.

Author's Comments: "Losing one copy of the MIR15A/MIR16-1 gene appears to promote tumor cell proliferation in both mice and patients," said Chesi. "For many years, we thought that deletion of chromosome 13 was just a byproduct of other genetic changes in the tumor and that it did not directly affect disease progression. Our study now demonstrates that deletion of chromosome 13, and specifically deletion of MIR15A/MIR16-1, appears to alter the biology of the tumor.

"However, the fact that the entire chromosome 13, and not just MIR15A/MIR16-1, is lost in many cases of MGUS or multiple myeloma suggests that other genes on this chromosome are also likely to be important for pathogenesis," added Chesi. In particular, Chesi is interested in studying DIS3, another gene located on chromosome 13 that is frequently mutated in multiple myeloma. The authors were not able to assess its contribution in this study due to the lack of relevant mouse models.
-end-
Study Limitations: A limitation of the study is that it was not possible to delete Rb1 or miR15a/miR16-1 only in myeloma cells due to technical restrictions of their mouse model. As a result, these genes were deleted in all cells, including immune cells, which could have led to indirect effects on disease progression, explained Chesi. However, Chesi added that results from additional control experiments indicate that the observed results are unlikely to be indirect, as transplanted tumors behaved similarly in both wild-type and miR15a/miR16-1-deleted mice.

Funding & Disclosures: This study was sponsored by grants from the National Institutes of Health. Chesi declares no conflict of interest.

American Association for Cancer Research

Related Cancer Articles:

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.
Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.
Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.
Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.
Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.
Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.
More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.
New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.
American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.
Oncotarget: Cancer pioneer employs physics to approach cancer in last research article
In the cover article of Tuesday's issue of Oncotarget, James Frost, MD, PhD, Kenneth Pienta, MD, and the late Donald Coffey, Ph.D., use a theory of physical and biophysical symmetry to derive a new conceptualization of cancer.
More Cancer News and Cancer Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Sound And Silence
Sound surrounds us, from cacophony even to silence. But depending on how we hear, the world can be a different auditory experience for each of us. This hour, TED speakers explore the science of sound. Guests on the show include NPR All Things Considered host Mary Louise Kelly, neuroscientist Jim Hudspeth, writer Rebecca Knill, and sound designer Dallas Taylor.
Now Playing: Science for the People

#576 Science Communication in Creative Places
When you think of science communication, you might think of TED talks or museum talks or video talks, or... people giving lectures. It's a lot of people talking. But there's more to sci comm than that. This week host Bethany Brookshire talks to three people who have looked at science communication in places you might not expect it. We'll speak with Mauna Dasari, a graduate student at Notre Dame, about making mammals into a March Madness match. We'll talk with Sarah Garner, director of the Pathologists Assistant Program at Tulane University School of Medicine, who takes pathology instruction out of...
Now Playing: Radiolab

Kittens Kick The Giggly Blue Robot All Summer
With the recent passing of Ruth Bader Ginsburg, there's been a lot of debate about how much power the Supreme Court should really have. We think of the Supreme Court justices as all-powerful beings, issuing momentous rulings from on high. But they haven't always been so, you know, supreme. On this episode, we go all the way back to the case that, in a lot of ways, started it all.  Support Radiolab by becoming a member today at Radiolab.org/donate.