HIGHLIGHTSd Cross-sectional study of 44 hospitalized COVID-19 patients d RBD-specific IgG responses detectable in all patients 6 days after PCR confirmation d Neutralizing titers are detectable in all patients 6 days after PCR confirmation d RBD-specific IgG titers correlate with the neutralizing potency

By misdirecting the activity of Activation-Induced Deaminase (AID) to a conditional MYC transgene, we have achieved sporadic, AID-dependent MYC activation in germinal center B cells of Vk*MYC mice. Whereas control C57BL/6 mice develop benign monoclonal gammopathy with age, all Vk*MYC mice progress to an indolent multiple myeloma associated with the biological and clinical features highly characteristic of the human disease. Furthermore, antigen-dependent myeloma could be induced by immunization with a T-dependent antigen. Consistent with these findings in mice, more frequent MYC rearrangements, elevated levels of MYC mRNA, and MYC target genes distinguish human patients with multiple myeloma from individuals with monoclonal gammopathy, implicating a causal role for MYC in the progression of monoclonal gammopathy to multiple myeloma.

28SARS-CoV-2 is currently causing a devastating pandemic and there is a pressing need to 29 understand the dynamics, specificity, and neutralizing potency of the humoral immune response 30 during acute infection. Herein, we report the dynamics of antibody responses to the receptor-31 binding domain (RBD) of the spike protein and virus neutralization activity in 44 COVID-19 32 patients. RBD-specific IgG responses were detectable in all patients 6 days after PCR 33 confirmation. Using a clinical isolate of SARS-CoV-2, neutralizing antibody titers were also 34 detectable in all patients 6 days after PCR confirmation. The magnitude of RBD-specific IgG 35 binding titers correlated strongly with viral neutralization. In a clinical setting, the initial analysis of 36 the dynamics of RBD-specific IgG titers was corroborated in a larger cohort of PCR-confirmed 37 patients (n=231). These findings have important implications for our understanding of protective 38 immunity against SARS-CoV-2, the use of immune plasma as a therapy, and the development of 39 much-needed vaccines. 40 41

MYC locus rearrangements – often complex combinations of translocations, insertions, deletions, and inversions - in multiple myeloma (MM) were thought to be a late progression event, which often did not involve immunoglobulin genes. Yet germinal center activation of MYC expression has been reported to cause progression to MM in an MGUS prone mouse strain. Although previously detected in 16% of MM, we find MYC rearrangements in nearly 50% of MM, including smoldering MM, and they are heterogeneous in some cases. Rearrangements reposition MYC near a limited number of genes associated with conventional enhancers, but mostly with super-enhancers (e.g., IGH, IGL, IGK, NSMCE2, TXNDC5, FAM46C, FOXO3, IGJ, PRDM1). MYC rearrangements are associated with a significant increase of MYC expression that is monoallelic, but MM tumors lacking a rearrangement have bi-allelic MYC expression at significantly higher levels than in MGUS. We also show that germinal center activation of MYC does not cause MM in a mouse strain that rarely develops spontaneous MGUS. It appears that increased MYC expression at the MGUS/MM transition usually is bi-allelic, but sometimes can be mono-allelic if there is a MYC rearrangement. Our data suggests that MYC rearrangements, regardless of when they occur during MM pathogenesis, provide one event that contributes to tumor autonomy.