The Chromosome 13 Conundrum in Multiple Myeloma Brian A

Views

In the Spotlight The Chromosome 13 Conundrum in Multiple Myeloma Brian A. Walker Summary: In this issue of Blood Cancer Discovery, Chesi and colleagues have performed a series of mouse experiments, combined with patient sample analysis, to delineate the role of del(13) in multiple myeloma. They identify loss of the miRNA cluster MIR15A/16-1 as critical for myelomagenesis and progression of disease.

See related article by Chesi et al., p. 68 (1).

In this issue of Blood Cancer Discovery, Chesi and col- Here, the authors use the Vk*MYC mouse model to further leagues use mouse models to unravel the important loci on interrogate the role of chromosome 13 abnormalities. The chromosome 13 in multiple myeloma (1). Chromosome 13 Vk*MYC model results in activation of MYC expression via is deleted in approximately 50% of patients with newly diag- somatic hypermutation in germinal center B cells, causing nosed multiple myeloma. However, despite being the most an indolent multiple myeloma with biological and clinical common copy-number change, its association with prognosis features of the human disease (8). Similar to human multiple has been debated. Initially, del(13) was associated with a poor myeloma plasma cells, the mouse multiple myeloma plasma outcome, but further study of high-risk abnormalities that cells have frequent copy-number changes, including loss of co-occur with del(13), such as t(4;14), led to the conclusion mouse chromosome 14, which includes a region syntenic that it is not associated with poor prognosis (2). In multiple to human chromosome 13 containing Dis3, Rb1, and the myeloma, the main genes of interest on chromosome 13 Mir15a/16-1 cluster. have been the cell-cycle regulator RB1 and the exonuclease By crossing the Vk*MYC mice with constitutive Rb1het mice DIS3. RB1 is infrequently mutated but is more frequently bi- that lack one allele of Rb1, the authors show that haploinsuf- allelically deleted (6%), especially in high-risk groups (3). In ficiency ofRb1 does not accelerate multiple myeloma initia- contrast, DIS3 is one of the most frequently mutated genes tion or progression. However, by crossing the Vk*MYC mice in multiple myeloma (10%), and biallelic abnormalities are with those with homozygous deletions of the Mir15a/16-1 associated with poor outcome (4, 5). However, due to the cluster (Vk*MYCxMIR) they show a significant decrease in high frequency of whole-arm deletion of chromosome 13, the time that the mice take to develop an M-spike and also and infrequent mutations of the genes contained within, it shorten survival of those mice. Loss of the Mir15a/16-1 cluster has been difficult to determine a minimally altered region on accelerated the manifestation of clonal plasma cells and pro- this chromosome. moted extramedullary disease. In chronic lymphocytic leukemia (CLL) a similar problem To provide further evidence for the importance of the exists with frequent deletion of chromosome 13, but it is miRNA cluster, the authors looked at the clonal plasma cells surprisingly associated with a favorable outcome. Unlike in the Vk*MYCxMIR crossed mice. These plasma cells do not in multiple myeloma, studies examining del(13) in CLL have deletion of the rest of the chromosome, which contains have identified a recurrently minimally deleted region that Rb1 and Dis3, and so chromosomal loss falls from 23% in includes the miRNA cluster containing MIR15A and MIR16-1 Vk*MYC mice to 0% in the Vk*MYCxMIR mice, indicating (6), which have been shown to regulate the expression of that loss of Mir15a/16-1 drives selection for loss of the chro- several cell-cycle genes including CCND1, CCND2, CDK4, mosome. Also, no mutations of Dis3 or Rb1 were detected in CDK6, CHK1, and CDC25A (7). In addition, MIR15A/16-1 and the Vk*MYCxMIR mice. Taken together, the authors conclude BCL2 expression levels are inversely correlated in CLL. Mouse that loss of the Mir15a/16-1 cluster promotes myelomagenesis. strains were developed with loss of Mir15A/16-1 to study the To validate their findings in mouse models, the authors effect of this locus in lymphoproliferative diseases (7). Given also analyzed patient genomic datasets. They found del(13) the similarities between multiple myeloma and CLL regard- in monoclonal gammopathy of undetermined significance ing chromosome 13 deletion, it is surprising that there have and multiple myeloma patient samples at similar frequencies been relatively few reports on the biological or prognostic in most myeloma subgroups, indicating that loss of the chro- impact of MIR15A/16-1 in multiple myeloma. mosome is an early event and contributes to immortaliza- tion of the clone. In patients with newly diagnosed multiple myeloma they identified the most frequent region of deletion Indiana University - Purdue University Indianapolis, Indianapolis, Indiana. occurs around RB1 and MIR15A/16-1, with copy number– Corresponding Author: Brian A. Walker, Indiana University - Purdue dependent expression of MIR15A. By stratifying patients University Indianapolis, 975 W. Walnut Street, IB 544B, Indianapolis, IN based on copy-number changes of MIR15A/16-1, the authors 46202. Phone: 317-278-7733; Fax: 317-274-0396; E-mail: [email protected] compared gene expression profiles and identified increased Blood Cancer Discov 2020;1:16–17 expression of CCND2 in samples with loss of MIR15A/16-1, as doi: 10.1158/2643-3249.BCD-20-0081 well as an association with increased expression of prolifera- ©2020 American Association for Cancer Research. tion and nuclear transport markers.

16 | BLOOD CANCER DISCOVERY july 2020 AACRJournals.org

Although the authors present a clear role for MIR15A/16-1 more questions arise about how this miRNA cluster allows in myelomagenesis, they also point out that there can be myelomagenesis to occur and how this information can be additional roles for the other genes of interest on chromo- used to benefit patient outcome and potentially prevention some 13. Homozygous deletion of RB1 is associated with of the disease. In addition, it remains unclear what is impor- poor prognosis in patients and is selected for during multi- tant for myelomagenesis in patients without del(13), where ple myeloma progression, as well as in several mouse mod- MIR15A/16-1 remains intact. Are there other miRNAs with a els. DIS3 is among the most commonly mutated genes in similar function being dysregulated on other chromosomes? multiple myeloma, with hotspots of mutation consistent with a change in function. Both of these genes are clearly Disclosure of Potential Conflicts of Interest important in the biology of the disease and require further No potential conflicts of interest were disclosed. study to determine how the abnormalities are important. It would also be interesting to explore the interaction of DIS3, Published first June 22, 2020. RB1, and MIR15A/16-1 abnormalities because they are subject to the same chromosomal losses. Additional mouse model crosses, or CRISPR engineering, could be useful tools to References examine these interactions on disease progression. . 1 Chesi M, Stein CK, Garbitt VM, Sharik ME, Asmann YW, Bergsagel Now that the importance of MIR15A/16-1 in the initiation M, et al. Monosomic loss of MIR15A/MIR16-1 is a driver of multiple myeloma proliferation and disease progression. Blood Cancer Discov and biology of multiple myeloma has been established, we can 2020;1:68–81. learn valuable lessons from the extensive work performed in 2. Walker BA, Leone PE, Chiecchio L, Dickens NJ, Jenner MW, Boyd KD, CLL on the same cluster. Because of the nature of miRNAs, et al. A compendium of myeloma-associated chromosomal copy num- it is currently difficult to deliver these into cells to act as drugs ber abnormalities and their prognostic value. Blood 2010;116:e56–65. and restore their function, but instead downstream targets 3. Chavan SS, He J, Tytarenko R, Deshpande S, Patel P, Bailey M, et al. can be used as therapeutic options. In CLL, loss of the miRNA Bi-allelic inactivation is more prevalent at relapse in multiple myeloma, identifying RB1 as an independent prognostic marker. Blood cluster is associated with proliferation and increased expres- Cancer J 2017;7:e535. sion of the antiapoptotic inhibitor BCL2. In multiple mye- 4. Boyle EM, Ashby C, Tytarenko R, Deshpande S, Wang Y, Sawyer J, loma, the authors also saw increased expression of BCL2 in et al. BRAF and DIS3 mutations associate with adverse outcome in a patients with loss of MIR15A/16-1. The BCL2 inhibitor vene- long-term follow-up of patients with multiple myeloma. Clin Cancer toclax has recently had success in the treatment of multiple Res 2020;26:2422–32. myeloma, with response rates >95% in t(11;14) patients (9). It 5. Chapman MA, Lawrence MS, Keats JJ, Cibulskis K, Sougnez C, has also been used in the treatment of patients with CLL with Schinzel AC, et al. Initial genome sequencing and analysis of multiple myeloma. Nature 2011;471:467–72. great success (10). The identification of loss ofMIR15A/16-1 in 6. Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, et al. multiple myeloma may also indicate a benefit for this group of Frequent deletions and down-regulation of micro- RNA genes miR15 patients and could easily be tested using existing trial samples. and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Although there are similarities with CLL and multiple mye- Acad Sci U S A 2002;99:15524–9. loma, there are also likely to be differences given the different 7. Klein U, Lia M, Crespo M, Siegel R, Shen Q, Mo T, et al. The DLEU2/ B-cell backgrounds. Although the main target of mir15A/16-1 miR-15a/16-1 cluster controls B cell proliferation and its deletion leads to chronic lymphocytic leukemia. Cancer Cell 2010;17:28–40. is BCL2 in CLL, there may be other targets in multiple mye- 8. Chesi M, Robbiani DF, Sebag M, Chng WJ, Affer M, Tiedemann R, loma that are worth exploring further as therapeutic targets. et al. AID-dependent activation of a MYC transgene induces multi- In summary, Chesi and colleagues provide insight into ple myeloma in a conditional mouse model of post-germinal center the importance of del(13), noncoding RNAs, and the initia- malignancies. Cancer Cell 2008;13:167–80. tion of multiple myeloma. They identified a key role in the 9. Moreau P, Harrison S, Cavo M, De la Rubia J, Popat R, Gasparetto C, miRNA cluster MIR15A/16-1 in disease initiation, but do not et al. Updated analysis of Bellini, a phase 3 study of venetoclax or pla- cebo in combination with bortezomib and dexamethasone in patients rule out the other key genes on chromosome 13 as important with relapsed/refractory multiple myeloma. Blood 2019;134:1888. drivers of progression. Clearly, one important question has 10. Jain N, Keating M, Thompson P, Ferrajoli A, Burger J, Borthakur G, been answered regarding the conundrum of chromosome et al. Ibrutinib and venetoclax for first-line treatment of CLL. N Engl 13 in multiple myeloma, but, as is the way with research, J Med 2019;380:2095–103.

july 2020 BLOOD CANCER DISCOVERY | 17

Brian A. Walker

Blood Cancer Discov 2020;1:16-17.

Updated version Access the most recent version of this article at: http://bloodcancerdiscov.aacrjournals.org/content/1/1/16

Cited articles This article cites 10 articles, 4 of which you can access for free at: http://bloodcancerdiscov.aacrjournals.org/content/1/1/16.full#ref-list-1

E-mail alerts Sign up to receive free email-alerts related to this article or journal.

Reprints and To order reprints of this article or to subscribe to the journal, contact the AACR Publications Subscriptions Department at [email protected].

Permissions To request permission to re-use all or part of this article, use this link http://bloodcancerdiscov.aacrjournals.org/content/1/1/16. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC) Rightslink site.