Loss of Specific Gene May Help Drive Myeloma Progression, Study Finds

One of the most common genomic defects in multiple myeloma patients is the loss of one copy of chromosome 13, and researchers now suggest that the loss of one particular gene during that process initiates a cascade of cell division events that promotes myeloma progression.

This gene codes for two microRNAs — MIR15A/MIR16-1 — small RNA molecules controlling genes involved in B-cell proliferation. When one copy was absent in mice, the animals developed myeloma features faster, their cancers were more aggressive, and their survival rates were lower.

Their study, “Monosomic Loss of MIR15A/MIR16-1 Is a Driver of Multiple Myeloma Proliferation and Disease Progression,” was published in the journal Blood Cancer Discovery.

The loss of chromosome 13 or a part of that chromosome is seen in about 40% of all multiple myeloma patients. But exactly how that genomic defect influences the risk of developing myeloma or patient outcomes is still controversial.

The region of chromosome 13 that is often lost shelters several genes involved in B-cell proliferation. Among them are the genes coding for RB1, known to be inactive in many cancers, and MIR15A/MIR16-1. While not yet linked to myeloma, studies point to a role for MIR15A/MIR16-1 in diseases of plasma cells — the particular B-cell subset that causes myeloma.

Researchers at the Mayo Clinic investigated if changes to these individual genes could be responsible for the initiation and progression of the disease.

“The purpose of our study was to model genetic risk factors that may contribute to initiation and progression of multiple myeloma,” Marta Chesi, PhD, the lead author of the study and an associate professor at the Mayo Clinic, said in a press release. “This understanding could eventually allow us to identify the mechanisms that increase the risk of progressing to multiple myeloma.”

Researchers used a strain of mice that mimics many features of the disease, including plasma cell proliferation, anemia, bone disease, and elevated levels of monoclonal protein — an antibody that is produced by plasma cells. One particular warning sign of myeloma is an M spike; an abnormally high level of this protein.

The strain was developed by the same group of researchers at the Mayo Clinic, and has been confirmed as a highly accurate model of myeloma in independent studies.

They studied what happened to animals when one copy of either of two genes was removed from their genome. While RB1 loss did not contribute to myeloma progression, the loss of one copy of the Mir15A/Mir16-1 cluster significantly accelerated both myeloma and its precursor condition, monoclonal gammopathy of undetermined significance (MGUS).

Consistently, mice lacking one copy of this cluster gene lived a median of 90 weeks, seven weeks less than animals with two copies of this gene. The effect was cumulative, as those lacking the two copies of the Mir15A/Mir16-1 cluster lived only 68 weeks.

After ruling out changes in the microenvironment as amain cause of disease progression in mice without one copy of the Mir15A/Mir16-1 cluster, researchers found that several genes involved in cell division and DNA replication were increased in plasma cells of the myeloma mice. The genes are direct targets of Mir15A/Mir16-1, but in the absence of these microRNAs become overly expressed, causing plasma cells to proliferate uncontrollably.

“Losing one copy of the MIR15A/MIR16-1 gene appears to promote tumor cell proliferation in both mice and patients,” Chesi said. “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,” she added.

Researchers then acquired tissue samples from myeloma or MGUS patients. These cells not only showed lower levels of miR15-A/miR16-1, but also elevated levels of the same cell division genes that were higher in the animals’ plasma cells.

These findings indicated that the deletion of MIR15A/MIR16-1 accelerates the progression of myeloma in mouse models, and possibly people. But as large portions of chromosome 13 are typically deleted in myeloma patients, researchers believe other genes there may also contribute to the disease.

“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,” Chesi said.

The research team is interested in studying the gene DIS3, which has also been implicated in myeloma cases. But mouse models necessary to test this gene are lacking.