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Faster B-cell repletion after anti-CD20 infusion in Black patients compared to white patients with neurologic diseases [Letter]

Saidenberg, Lucia; Arbini, Arnaldo A; Silverman, Gregg J; Lotan, Itay; Cutter, Gary; Kister, Ilya
This retrospective, single-center study aimed to characterize and compare the kinetics of B-cell reemergence following anti-CD20 infusion (anti-CD20i) in African American (AA) and white patients with MS or NMOSD. In a logistic regression model that included race, time since anti-CD20i, body mass index, and diagnosis, only AA race (p=0.01) and time since anti-CD20i (p=0.0003) were significant predictors of B-cell repletion. However, B-cell subset composition was similar between AA and white patients with detectable CD19+ B-cell counts. These findings highlight the importance of including a diverse study population in future studies of anti-CD20 therapies.
PMID: 35490448
ISSN: 2211-0356
CID: 5215682

EMSY inhibits homologous recombination repair and the interferon response, promoting lung cancer immune evasion

Marzio, Antonio; Kurz, Emma; Sahni, Jennifer M; Di Feo, Giuseppe; Puccini, Joseph; Jiang, Shaowen; Hirsch, Carolina Alcantara; Arbini, Arnaldo A; Wu, Warren L; Pass, Harvey I; Bar-Sagi, Dafna; Papagiannakopoulos, Thales; Pagano, Michele
Non-small cell lung cancers (NSCLCs) harboring KEAP1 mutations are often resistant to immunotherapy. Here, we show that KEAP1 targets EMSY for ubiquitin-mediated degradation to regulate homologous recombination repair (HRR) and anti-tumor immunity. Loss of KEAP1 in NSCLC induces stabilization of EMSY, producing a BRCAness phenotype, i.e., HRR defects and sensitivity to PARP inhibitors. Defective HRR contributes to a high tumor mutational burden that, in turn, is expected to prompt an innate immune response. Notably, EMSY accumulation suppresses the type I interferon response and impairs innate immune signaling, fostering cancer immune evasion. Activation of the type I interferon response in the tumor microenvironment using a STING agonist results in the engagement of innate and adaptive immune signaling and impairs the growth of KEAP1-mutant tumors. Our results suggest that targeting PARP and STING pathways, individually or in combination, represents a therapeutic strategy in NSCLC patients harboring alterations in KEAP1.
PMID: 34963055
ISSN: 1097-4172
CID: 5108142

Improving prognostic assignment in older adults with multiple myeloma using acquired genetic features, clonal hemopoiesis and telomere length

Boyle, Eileen M; Williams, Louis; Blaney, Patrick; Ashby, Cody; Bauer, Michael; Walker, Brian A; Ghamlouch, Hussein; Choi, Jinyoung; Perrial, Emeline; Wang, Yubao; Caro, Jessica; Stoeckle, James H; Arbini, Arnaldo; Kaminetzky, David; Braunstein, Marc; Bruno, Benedetto; Razzo, Beatrice; Diamond, Benjamin; Maclachlan, Kylee; Maura, Francesco; Landgren, Ola; Litke, Rachel; Fegan, Christopher D; Keats, Johnathan; Auclair, Daniel; Davies, Faith E; Morgan, Gareth J
PMID: 34148053
ISSN: 1476-5551
CID: 4918002

Loss of FBXO31-mediated degradation of DUSP6 dysregulates ERK and PI3K-AKT signaling and promotes prostate tumorigenesis

Duan, Shanshan; Moro, Loredana; Qu, Rui; Simoneschi, Daniele; Cho, Hyunwoo; Jiang, Shaowen; Zhao, Huiyong; Chang, Qing; de Stanchina, Elisa; Arbini, Arnaldo A; Pagano, Michele
FBXO31 is the substrate receptor of one of many CUL1-RING ubiquitin ligase (CRL1) complexes. Here, we show that low FBXO31 mRNA levels are associated with high pre-operative prostate-specific antigen (PSA) levels and Gleason grade in human prostate cancer. Mechanistically, the ubiquitin ligase CRL1FBXO31 promotes the ubiquitylation-mediated degradation of DUSP6, a dual specificity phosphatase that dephosphorylates and inactivates the extracellular-signal-regulated kinase-1 and -2 (ERK1/2). Depletion of FBXO31 stabilizes DUSP6, suppresses ERK signaling, and activates the PI3K-AKT signaling cascade. Moreover, deletion of FBXO31 promotes tumor development in a mouse orthotopic model of prostate cancer. Treatment with BCI, a small molecule inhibitor of DUSP6, suppresses AKT activation and prevents tumor formation, suggesting that the FBXO31 tumor suppressor activity is dependent on DUSP6. Taken together, our studies highlight the relevance of the FBXO31-DUSP6 axis in the regulation of ERK- and PI3K-AKT-mediated signaling pathways, as well as its therapeutic potential in prostate cancer.
PMID: 34686346
ISSN: 2211-1247
CID: 5031132

CRL4AMBRA1 is a master regulator of D-type cyclins

Simoneschi, Daniele; Rona, Gergely; Zhou, Nan; Jeong, Yeon-Tae; Jiang, Shaowen; Milletti, Giacomo; Arbini, Arnaldo A; O'Sullivan, Alfie; Wang, Andrew A; Nithikasem, Sorasicha; Keegan, Sarah; Siu, Yik; Cianfanelli, Valentina; Maiani, Emiliano; Nazio, Francesca; Cecconi, Francesco; Boccalatte, Francesco; Fenyö, David; Jones, Drew R; Busino, Luca; Pagano, Michele
D-type cyclins are central regulators of the cell division cycle and are among the most frequently deregulated therapeutic targets in human cancer1, but the mechanisms that regulate their turnover are still being debated2,3. Here, by combining biochemical and genetics studies in somatic cells, we identify CRL4AMBRA1 (also known as CRL4DCAF3) as the ubiquitin ligase that targets all three D-type cyclins for degradation. During development, loss of Ambra1 induces the accumulation of D-type cyclins and retinoblastoma (RB) hyperphosphorylation and hyperproliferation, and results in defects of the nervous system that are reduced by treating pregnant mice with the FDA-approved CDK4 and CDK6 (CDK4/6) inhibitor abemaciclib. Moreover, AMBRA1 acts as a tumour suppressor in mouse models and low AMBRA1 mRNA levels are predictive of poor survival in cancer patients. Cancer hotspot mutations in D-type cyclins abrogate their binding to AMBRA1 and induce their stabilization. Finally, a whole-genome, CRISPR-Cas9 screen identified AMBRA1 as a regulator of the response to CDK4/6 inhibition. Loss of AMBRA1 reduces sensitivity to CDK4/6 inhibitors by promoting the formation of complexes of D-type cyclins with CDK2. Collectively, our results reveal the molecular mechanism that controls the stability of D-type cyclins during cell-cycle progression, in development and in human cancer, and implicate AMBRA1 as a critical regulator of the RB pathway.
PMID: 33854235
ISSN: 1476-4687
CID: 4846192

The molecular make up of smoldering myeloma highlights the evolutionary pathways leading to multiple myeloma

Boyle, Eileen M; Deshpande, Shayu; Tytarenko, Ruslana; Ashby, Cody; Wang, Yan; Bauer, Michael A; Johnson, Sarah K; Wardell, Christopher P; Thanendrarajan, Sharmilan; Zangari, Maurizio; Facon, Thierry; Dumontet, Charles; Barlogie, Bart; Arbini, Arnaldo; Rustad, Even H; Maura, Francesco; Landgren, Ola; Zhan, Fenghuang; van Rhee, Frits; Schinke, Carolina; Davies, Faith E; Morgan, Gareth J; Walker, Brian A
Smoldering myeloma (SMM) is associated with a high-risk of progression to myeloma (MM). We report the results of a study of 82 patients with both targeted sequencing that included a capture of the immunoglobulin and MYC regions. By comparing these results to newly diagnosed myeloma (MM) we show fewer NRAS and FAM46C mutations together with fewer adverse translocations, del(1p), del(14q), del(16q), and del(17p) in SMM consistent with their role as drivers of the transition to MM. KRAS mutations are associated with a shorter time to progression (HR 3.5 (1.5-8.1), p = 0.001). In an analysis of change in clonal structure over time we studied 53 samples from nine patients at multiple time points. Branching evolutionary patterns, novel mutations, biallelic hits in crucial tumour suppressor genes, and segmental copy number changes are key mechanisms underlying the transition to MM, which can precede progression and be used to guide early intervention strategies.
PMID: 33436579
ISSN: 2041-1723
CID: 4771132

Improving prognostic assignment in older age groups of multiple myeloma [Meeting Abstract]

Boyle, E. M.; Litke, R. R.; Blaney, P.; Ashby, T. C.; Bauer, M.; Walker, B.; Ghamlouch, H.; Choi, J.; Perrial, E.; Wang, Y.; Caro, J.; Stoeckle, J.; Arbini, A.; Kaminetsky, D.; Braunstein, M.; Bruno, B.; Razzo, B.; Maclachlan, K.; Maura, E.; Landgren, C. O.; Williams, L.; Fegan, C.; Keats, J.; Davies, F. E.; Morgan, G. J.
ISSN: 0002-8614
CID: 5389142

Multiomic Mapping of Copy Number and Structural Variation on Chromosome 1 (Chr1) Highlights Multiple Recurrent Disease Drivers [Meeting Abstract]

Blaney, Patrick; Boyle, Eileen M.; Wang, Yubao; Ghamlouch, Hussein; Choi, Jinyoung; Williams, Louis; James, Stoeckle; Siegel, Ariel; Razzo, Beatrice; Braunstein, Marc; Kaminetzky, David; Arbini, Arnaldo A.; Bruno, Benedetto; Corre, Jill; Montes, Lydia; Auclair, Daniel; Davies, Faith E.; Tsirigos, Aristotelis; Rustad, Even H.; Maura, Francesco; Landgren, Ola; Bauer, Michael A.; Walker, Brian; Morgan, Gareth
ISSN: 0006-4971
CID: 5389172

Unifying the Definition of High-Risk in Multiple Myeloma [Meeting Abstract]

Siegel, Ariel; Boyle, Eileen M.; Blaney, Patrick; Wang, Yubao; Ghamlouch, Hussein; Choi, Jinyoung; Caro, Jessica; Williams, Louis; Razzo, Beatrice; Arbini, Arnaldo A.; Braunstein, Marc; Kaminetzky, David; Auclair, Daniel; Pawlyn, Charlotte; Cairns, David; Jackson, Graham; Walker, Brian; Bruno, Benedetto; Morgan, Gareth J.; Davies, Faith E.
ISSN: 0006-4971
CID: 5389182

Hispanic or Latin American Ancestry Is Associated with a Similar Genomic Profile and a Trend Toward Inferior Outcomes in Newly Diagnosed Multiple Myeloma As Compared to Non-Hispanic White Patients in the Multiple Myeloma Research Foundation (MMRF) CoMMpassstudy [Meeting Abstract]

Williams, Louis; Blaney, Patrick; Boyle, Eileen M.; Ghamlouch, Hussein; Wang, Yubao; Choi, Jinyoung; Bauer, Michael A.; Siegel, Ariel; Stoeckle, James; Razzo, Beatrice; Auclair, Daniel; Kaminetzky, David; Braunstein, Marc; Bruno, Benedetto; Arbini, Arnaldo A.; Walker, Brian A.; Davies, Faith E.; Morgan, Gareth J.
ISSN: 0006-4971
CID: 5389192