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. 2020 Jan;34(1):322-326.
doi: 10.1038/s41375-019-0543-4. Epub 2019 Aug 22.

MYC dysregulation in the progression of multiple myeloma

Kristine Misund #  1   2 , Niamh Keane #  1   3 , Caleb K Stein  1 , Yan W Asmann  4 , Grady Day  1 , Seth Welsh  1 , Scott A Van Wier  1 , Daniel L Riggs  1 , Greg Ahmann  1 , Marta Chesi  1 , David S Viswanatha  5 , Shaji K Kumar  5 , Angela Dispenzieri  5 , Veronica Gonzalez-Calle  1 , Robert A Kyle  5 , Michael O'Dwyer  3 , S Vincent Rajkumar  5 , K Martin Kortüm  6 , J Jonathan Keats  7 ; MMRF CoMMpass Network; Rafael Fonseca  1 , A Keith Stewart  1 , W Michael Kuehl  8 , Esteban Braggio  1 , P Leif Bergsagel  9
Affiliations

MYC dysregulation in the progression of multiple myeloma

Kristine Misund et al. Leukemia. 2020 Jan.
No abstract available

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Conflict of interest statement

Conflict of Interest Disclosures

Rafael Fonseca works as a consultant for AMGEN, BMS, Celgene, Takeda, Bayer, Jansen, Pharmacyclics, Merck, Sanofi, Kite and Juno.

He is on the board of Scientific Advisory Board: Adaptive Biotechnologies.

Mayo Clinic and Rafael Fonseca hold a patent for prognosticating myeloma using FISH.

None of the authors have interests to disclose.

Figures

Figure 1.
Figure 1.. Location of MYC breakpoints and variation in MYC expression
The exact location of breakpoints (black dots) at the MYC locus for the 260 NDMM cases with MYC SV in the CoMMpass cohort, shows that the breakpoints clustered within an approximately 2Mb region around MYC, with three breakpoint cluster regions: one centered on MYC, a less frequent one centromeric, and more common one telomeric to MYC. The level of MYC expression (log transform of Salmon TPM) is shown on the Y-axis, and shows that the breakpoints were associated with an increased expression of MYC, (A). The level of MYC expression is highest in cases with IG or Non-IG MYC SVs (median TPM 79; non-significant one-sided Wilcoxon test between IG and Non-IG MYC SVs, p-value > 0.05) according to data from 612 NDMM CoMMpass cases. Cases with IG or non-IG MYC SVs have significantly higher MYC expression than those with wholly confined telomeric MYC SVs (median TPM 38, p-value < 0.001), who in turn have significantly higher expression than cases with NFkB aberrations (median TPM 26, p-value < 0.05), and cases with RAS or FGFR3 mutations (median TPM 15) have low expression of MYC, even lower than cases with NFkB aberrations (p-value < 0.001). MYC expression is lowest in cases harboring MAX aberrations (median TPM 1, B). Across patients with MYC SVs, there was no correlation between the level of expression of MYC and NFkB aberrations or index (C and E). However, in patients without MYC SV, there is a significant correlation between the level of MYC TPM and the NFkB index (D and F). Vertical line in plots C and D denotes the median NFkBi. Correlation triangles report Spearman correlations between variables when highly significant (p-value < 0.001) with negative correlation in blue, positive correlation in red, and size of circle associated with absolute value of correlation.
Figure 2.
Figure 2.. Progression in SMM and NDMM and genomic copy number comparison of MGUS, SMM, and NDMM
An analysis of MYC SVs in SMM cohort revealed that MYC rearrangements that juxtaposed any of the Ig regions (five IgH, one IgL) had a rapid progression to MM (B). However, in NDMM, only cases with IgL MYC SVs had inferior outcomes (see also Supplementary Figure S1) Additionally, HRD cases harboring a Non-Ig MYC SV had a significant association with improved performance (B) not observed for Non-HRD (NHRD) cases (Supplementary Figures S2 and S3). Across 23 MGUS, 90 SMM, and 612 NDMM cases, the percent of samples with a gain and loss were determined at equal 30 Kb intervals across the entire genome. A gain was denoted if copy number segment values at given location was greater than log2(2.25/2) and loss if segment value was below log2(1.30/2). Across entire chromosomes, many of the copy number gains and losses are similarly prevalent across disease stages, however gain of 1q and loss of 13q significantly increase in frequency with disease stage, more so than any other chromosomes. (C)
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