Monosomic Loss of MIR15A/MIR16-1 Is a Driver of Multiple Myeloma Proliferation and Disease Progression

Abstract

The most common genetic abnormality in multiple myeloma (MM) is the deletion of chromosome 13, seen in almost half of newly diagnosed patients. Unlike chronic lymphocytic leukemia, where a recurrent minimally deleted region including <i>MIR15A/MIR16-1</i> has been mapped, the deletions in MM predominantly involve the entire chromosome and no specific driver gene has been identified. Additional candidate loci include <i>RB1</i> and <i>DIS3</i>, but while biallelic deletion of <i>RB1</i> is associated with disease progression, <i>DIS3</i> is a common essential gene and complete inactivation is not observed. The Vk*MYC transgenic mouse model of MM spontaneously acquires del(14), syntenic to human chromosome 13, and <i>Rb1</i> complete inactivation, but not <i>Dis3</i> mutations. Taking advantage of this model, we explored the role in MM initiation and progression of two candidate loci on chromosome 13: <i>RB1 and MIR15A/MIR16-1</i>. Monoallelic deletion of <i>Mir15a/Mir16-1</i> but not <i>Rb1</i> was sufficient to accelerate the development of monoclonal gammopathy in wildtype mice, and the progression of MM in Vk*MYC mice, resulting in increased expression of <i>Mir15a/Mir16-1</i> target genes and plasma cell proliferation, which was similarly observed in patients with MM.