Systematic characterization of therapeutic vulnerabilities in Multiple Myeloma with Amp1q reveals increased sensitivity to the combination of MCL1 and PI3K inhibitors.

The development of targeted therapy for patients with Multiple Myeloma (MM) is hampered by the low frequency of actionable genetic abnormalities. Gain or amplification of chr1q (Amp1q) is the most frequent arm-level copy number gain in patients with MM, and it is associated with higher risk of progression and death despite recent advances in therapeutics. Thus, developing targeted therapy for patients with MM and Amp1q stands to benefit a large portion of patients in need of more effective management. Here, we employed large-scale dependency screens and drug screens to systematically characterize the therapeutic vulnerabilities of MM with Amp1q and showed increased sensitivity to the combination of MCL1 and PI3K inhibitors. Using single-cell RNA sequencing, we compared subclones with and without Amp1q within the same patient tumors and showed that Amp1q is associated with higher levels of MCL1 and the PI3K pathway. Furthermore, by isolating isogenic clones with different copy number for part of the chr1q arm, we showed increased sensitivity to MCL1 and PI3K inhibitors with arm-level gain. Lastly, we demonstrated synergy between MCL1 and PI3K inhibitors and dissected their mechanism of action in MM with Amp1q.

Multiple Myeloma With Amplification of Chr1q: Therapeutic Opportunity and Challenges.

Multiple myeloma (MM) is an incurable plasma cell malignancy with a heterogeneous genetic background. Each MM subtype may have its own therapeutic vulnerabilities, and tailored therapy could improve outcomes. However, the cumulative frequency of druggable targets across patients is very low, which has precluded the widespread adoption of precision therapy for patients with MM. Amplification of the long arm of chromosome 1 (Amp1q) is one of the most frequent genetic alterations observed in patients with MM, and its presence predicts inferior outcomes in the era of proteasome inhibitors and immunomodulatory agents. Therefore, establishing precision medicine for MM patients with Amp1q stands to benefit a large portion of patients who are otherwise at higher risk of relapse. In this article, we review the prevalence and clinical significance of Amp1q in patients with MM, its pathogenesis and therapeutic vulnerabilities, and discuss the opportunities and challenges for Amp1q-targeted therapy.

The pattern of gene copy number alteration (CNAs) in hepatocellular carcinoma: an in silico analysis.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common type of liver cancer that occurs predominantly in patients with previous liver conditions. In the absence of an ideal screening modality, HCC is usually diagnosed at an advanced stage. Recent studies show that loss or gain of genomic materials can activate the oncogenes or inactivate the tumor suppressor genes to predispose cells toward carcinogenesis. Here, we evaluated both the copy number alteration (CNA) and RNA sequencing data of 361 HCC samples in order to locate the frequently altered chromosomal regions and identify the affected genes. RESULTS: Our data show that the chr1q and chr8p are two hotspot regions for genomic amplifications and deletions respectively. Among the amplified genes, YY1AP1 (chr1q22) possessed the largest correlation between CNA and gene expression. Moreover, it showed a positive correlation between CNA and tumor grade. Regarding deleted genes, CHMP7 (chr8p21.3) possessed the largest correlation between CNA and gene expression. Protein products of both genes interact with other cellular proteins to carry out various functional roles. These include ASH1L, ZNF496, YY1, ZMYM4, CHMP4A, CHMP5, CHMP2A and CHMP3, some of which are well-known cancer-related genes. CONCLUSIONS: Our in-silico analysis demonstrates the importance of copy number alterations in the pathology of HCC. These findings open a door for future studies that evaluate our results by performing additional experiments.