Chromothripsis in Treatment Resistance in Multiple Myeloma

Abstract

Multiple myeloma (MM) is a malignant disease caused by an abnormal proliferation of plasma cells, of which the prognostic factors include chromosomal abnormality, β-2 microglobulin, and albumin. Recently, the term chromothripsis has emerged, which is the massive but highly localized chromosomal rearrangement in response to a one-step catastrophic event. Many studies have shown an association of chromothripsis with the prognosis in several cancers; however, few studies have investigated it in MM. Here, we studied the association between chromothripsis-like patterns and treatment resistance or prognosis. First, we analyzed nine MM cell lines (U266, MM.1S, RPMI8226, KMS-11, KMS-12-BM, KMS-12-PE, KMS-28-BM, KMS-28-PE, and NCI-H929) and bone marrow samples of four patients who were diagnosed with MM by next-generation sequencing-based copy number variation analysis. The frequency of the chromothripsis-like pattern was observed in seven cell lines. We analyzed the treatment-induced chromothripsis-like patterns in KMS-12-BM and KMS-12-PE cells. As a result, breakpoints and chromothripsis-like patterns were increased after drug treatment in the relatively resistant KMS-12-BM. We further analyzed the patients’ results according to the therapeutic response, which was divided into sensitive and resistant, as suggested by the International Myeloma Working Group. The chromothripsis-like pattern was more frequently observed in the resistant group. In the sensitive group, the frequency of the chromothripsis-like pattern decreased after treatment, whereas the resistant group showed increased chromothripsis-like patterns after the treatment. These results suggest that the chromothripsis-like pattern is associated with treatment response in MM.

Venetoclax, bortezomib and S63845, an MCL1 inhibitor, in multiple myeloma

“… Keys: IC 50 , half‐maximal inhibitory concentration; BCL2, B‐cell CLL/lymphoma 2; MCL1, myeloid cell leukaemia 1; BCL2L1, BCL2 like 1; # References: , except unavailable amp(1q21) status for WL‐2. …”

Genome Instability in Multiple Myeloma: Facts and Factors

“…Chromothripsis is associated with known high-risk genetic alterations in MM, including IGH translocations involving MMSET , MAF , or MAFB ; biallelic inactivation of TP53 , deletion of 1p12, and high APOBEC mutational burden [ 619 ]. In addition to that, chromothripsis was associated with poor outcomes and was linked to treatment in MM [ 619 , 642 , 644 , 657 ]. For instance, chromothripsis occurs more often in patients with bortezomib-resistant MM that can be interpreted as a drug-induced response [ 657 ].…”

Somatic Genomic Mosaicism in Multiple Myeloma

“…MM patients display a high level of karyotype heterogeneity. Different patient genotypes can involve poly-aneuploidy, hyperdiploidy, hypodiploidy, chromosomal translocation, chaotic genomes (such as chromothripsis) ( Table 1), and/or a combination of other gene mutations and chromosomal aberrations (Garcia-Sanz et al, 1995;Avet-Loiseau et al, 2007;Klein et al, 2011;Magrangeas et al, 2011;Keats et al, 2012;Bolli et al, 2014;Lee et al, 2017;Kaur et al, 2018;Smetana et al, 2018;Ashby et al, 2019;Maura et al, 2019).…”

“…For example, within the stable micro-evolutionary phase, moderately treating cells is a better approach than maximal killing, as an over-killing strategy will trigger genome chaos, leading to rapid drug resistance (Heng, 2015(Heng, , 2019. MM resistance is frequently associated with chromothripsis (Lee et al, 2017) and likely involves treatmentinduced genome chaos. Thus, therapies using an adaptive strategy might confer better long-term benefits (Gatenby et al, 2009;Lohr et al, 2014).…”