The loss of one copy of a specific gene cluster could contribute to the initiation and progression of multiple myeloma, according to a new study. The research points to the gene cluster MIR15A/MIR16-1 as being key.
Writing online in Blood Cancer Discovery, Dr Marta Chesi, associate professor of medicine at the Mayo Clinic, USA, said the study modelled genetic risk factors that may contribute to initiation and progression of multiple myeloma. This could enable clinicians in the future to identify the mechanisms that increase the risk of progressing to multiple myeloma.
Multiple myeloma is preceded 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. However, the factors that contribute to progression are not well understood, the researchers say.
It is known that one copy of chromosome 13 is deleted in about half of MGUS and multiple myeloma patients. Therefore, Dr Chesi and her colleagues hypothesised that individual genes on chromosome 13 may promote disease initiation or progression.
They deleted a single copy of either Rb1 or miR15a/miR16-1 in wild-type mice and in a transgenic mouse model of multiple myeloma. The team found that deletion of one copy of Rb1 did not affect disease initiation or progression.
However, deleting one copy of miR15a/miR16-1 in wild-type mice significantly accelerated the development of an M-spike. The loss of one copy of miR15a/miR16-1 in mice with multiple myeloma also significantly enhanced the aggressiveness of the disease, leading to increased expression of genes that promote cellular proliferation.
“Losing one copy of the MIR15A/MIR16-1 gene appears to promote tumour cell proliferation in both mice and patients,” said Dr Chesi.
“For many years, we thought that deletion of chromosome 13 was just a by-product of other genetic changes in the tumour 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 tumour.
“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.”
Source: Chesi M, Stein CK, Garbitt VM, Sharik ME, Asmann YW, Bergsagel M, Riggs DL, Welsh SJ, Meermeier EW, Kumar SK, Braggio E, Bergsagel PL (2020) “Monosomic Loss of MIR15A/MIR16-1 Is a Driver of Multiple Myeloma Proliferation and Disease Progression”, Blood Cancer Discovery, doi: 10.1158/0008-5472.BCD-19-0068
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