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Acute Promyelocytic Leukemia With Torque Teno Mini Virus::RARA Fusion: An Approach to Screening and Diagnosis

Tsai, Harrison K; Sabbagh, Mark F; Montesion, Meagan; Williams, Erik A; Arbini, Arnaldo; Boué, Daniel R; Harris, Emily M; Wachter, Franziska; Grimmett, Leslie; Place, Andrew E; Lucas, Fabienne; Nardi, Valentina; Kim, Annette S; Brugnara, Carlo; Degar, Barbara; Pollard, Jessica; Harris, Marian H; Bledsoe, Jacob R
Acute promyelocytic leukemia (APL) with variant RARA translocation is linked to over 15 partner genes. Recent publications encompassing 6 cases have expanded the spectrum of RARA partners to torque teno mini virus (TTMV). This entity is likely underrecognized due to the lack of clinician and pathologist familiarity, inability to detect the fusion using routine testing modalities, and informatic challenges in its recognition within next-generation sequencing (NGS) data. We describe a clinicopathologic approach and provide the necessary tools to screen and diagnose APL with TTMV::RARA using existing clinical DNA- or RNA-based NGS assays, which led to the identification of 4 cases, all without other known cytogenetic/molecular drivers. One was identified prospectively and 3 retrospectively, including 2 from custom automated screening of multiple data sets (50,257 cases of hematopoietic malignancy, including 4809 acute myeloid leukemia/myeloid sarcoma/APL cases). Two cases presented as myeloid sarcoma, including 1 with multiple relapses after acute myeloid leukemia-type chemotherapy and hematopoietic stem cell transplant. Two cases presented as leukemia, had a poor response to induction chemotherapy, but achieved remission upon reinduction (including all-trans retinoic acid in 1 case) and subsequent hematopoietic stem cell transplant. Neoplastic cells demonstrated features of APL including frequent azurophilic granules and dim/absent CD34 and HLA-DR expression. RARA rearrangement was not detected by karyotype or fluorescent in situ hybridization. Custom analysis of NGS fusion panel data identified TTMV::RARA rearrangements and, in the prospectively identified case, facilitated monitoring in sequential bone marrow samples. APL with TTMV::RARA is a rare leukemia with a high rate of treatment failure in described cases. The diagnosis should be considered in leukemias with features of APL that lack detectable RARA fusions and other drivers, and may be confirmed by appropriate NGS tests with custom informatics. Incorporation of all-trans retinoic acid may have a role in treatment but requires accurate recognition of the fusion for appropriate classification as APL.
PMID: 38704030
ISSN: 1530-0285
CID: 5658272

Primary Colonic MALT Lymphomas Treated with Curative Endoscopic Mucosal Resection [Letter]

Nasir, Umair M; Arbini, Arnaldo A; Friedel, David M
PMID: 38056596
ISSN: 1538-2990
CID: 5595832

Genomic and immune signatures predict clinical outcome in newly diagnosed multiple myeloma treated with immunotherapy regimens

Maura, Francesco; Boyle, Eileen M; Coffey, David; Maclachlan, Kylee; Gagler, Dylan; Diamond, Benjamin; Ghamlouch, Hussein; Blaney, Patrick; Ziccheddu, Bachisio; Cirrincione, Anthony; Chojnacka, Monika; Wang, Yubao; Siegel, Ariel; Hoffman, James E; Kazandjian, Dickran; Hassoun, Hani; Guzman, Emily; Mailankody, Sham; Shah, Urvi A; Tan, Carlyn; Hultcrantz, Malin; Scordo, Michael; Shah, Gunjan L; Landau, Heather; Chung, David J; Giralt, Sergio; Zhang, Yanming; Arbini, Arnaldo; Gao, Qi; Roshal, Mikhail; Dogan, Ahmet; Lesokhin, Alexander M; Davies, Faith E; Usmani, Saad Z; Korde, Neha; Morgan, Gareth J; Landgren, Ola
Despite improving outcomes, 40% of patients with newly diagnosed multiple myeloma treated with regimens containing daratumumab, a CD38-targeted monoclonal antibody, progress prematurely. By integrating tumor whole-genome and microenvironment single-cell RNA sequencing from upfront phase 2 trials using carfilzomib, lenalidomide and dexamethasone with daratumumab ( NCT03290950 ), we show how distinct genomic drivers including high APOBEC mutational activity, IKZF3 and RPL5 deletions and 8q gain affect clinical outcomes. Furthermore, evaluation of paired bone marrow profiles, taken before and after eight cycles of carfilzomib, lenalidomide and dexamethasone with daratumumab, shows that numbers of natural killer cells before treatment, high T cell receptor diversity before treatment, the disappearance of sustained immune activation (that is, B cells and T cells) and monocyte expansion over time are all predictive of sustained minimal residual disease negativity. Overall, this study provides strong evidence of a complex interplay between tumor cells and the immune microenvironment that is predictive of clinical outcome and depth of treatment response in patients with newly diagnosed multiple myeloma treated with highly effective combinations containing anti-CD38 antibodies.
PMID: 37945755
ISSN: 2662-1347
CID: 5612852

African American patients with Multiple Sclerosis (MS) have higher proportions of CD19+ and CD20+ B-cell lineage cells in their cerebrospinal fluid than White MS patients

Xue, Haotian; Arbini, Arnaldo A.; Melton, Hunter J.; Kister, Ilya
ISSN: 2211-0348
CID: 5652472

African American patients with Multiple Sclerosis (MS) have higher proportions of CD19+ and CD20+ B-cell lineage cells in their cerebrospinal fluid than White MS patients

Xue, Haotian; Arbini, Arnaldo A; Melton, Hunter J; Kister, Ilya
OBJECTIVES/OBJECTIVE:To compare proportions of B-cell lineage CD19+ and CD20+ cells in CSF of African-American (AA) and White (W) patients with MS. BACKGROUND:AA MS patients are more likely to have oligoclonal bands in CSF, higher IgG index in CSF, and higher circulating plasmablasts in blood than W MS patients. It is unknown whether the proportion of B-cells in CSF differs between AA and W patients in MS. METHODS:Demographics, disease-related information, treatment history were retrospectively collected on patients with MS who self-identified as AA or W and underwent flow cytometry of CSF during diagnostic work-up. Proportion of B-lymphocytes, T-lymphocytes, NK cells, monocytes, and plasma cells were analyzed with flow cytometry. RESULTS:20 AA and 56 W MS patients fulfilled our inclusion criteria. The groups had similar demographics, CSF cell counts, protein and glucose CSF concentrations, and oligoclonal band number. IgG index was higher in AA compared to W (1.08 vs. 0.85, p = 0.031). AA had higher proportions of CD19+ (5.46 % AA vs. 2.26 % W, p = 0.006) and CD20+ (4.64 % AA vs. 1.91 % W, p = 0.004) cells but did not significantly differ in proportion of CD4+, CD8+, CD38+ bright B-cells, NK cells and monocytes. CONCLUSIONS:B-cells are overrepresented in the CSF of African American patients with MS relative to Whites.
PMID: 37832255
ISSN: 2211-0356
CID: 5604272

Multiomic mapping of acquired chromosome 1 copy number and structural variants to identify therapeutic vulnerabilities in multiple myeloma

Boyle, Eileen M; Blaney, Patrick; Stoeckle, James H; Wang, Yubao; Ghamlouch, Hussein; Gagler, Dylan; Braunstein, Marc; Williams, Louis; Tenenbaum, Avital; Siegel, Ariel; Chen, Xiaoyi; Varma, Gaurav; Avigan, Jason; Li, Alexander; Jinsi, Monica; Kaminetzky, David; Arbini, Arnaldo; Montes, Lydia; Corre, Jill; Rustad, Even H; Landgren, Ola; Maura, Francesco; Walker, Brian A; Bauer, Michael; Bruno, Benedetto; Tsirigos, Aristotelis; Davies, Faith E; Morgan, Gareth J
PURPOSE/OBJECTIVE:Chromosome 1 (chr1) copy number abnormalities (CNAs) and structural variants (SV) are frequent in newly diagnosed multiple myeloma (NDMM) and associate with a heterogeneous impact on outcome the drivers of which are largely unknown. EXPERIMENTAL DESIGN/METHODS:A multiomic approach comprising CRISPR, gene mapping of CNA and SV, methylation, expression, and mutational analysis was used to document the extent of chr1 molecular variants and their impact on pathway utilisation. RESULTS:We identified two distinct groups of gain(1q): focal gains associated with limited gene expression changes and a neutral prognosis, and whole-arm gains, which associate with substantial gene expression changes, complex genetics and an adverse prognosis. CRISPR identified a number of dependencies on chr1 but only limited variants associated with acquired CNAs. We identified seven regions of deletion, nine of gain, three of chromothripsis (CT) and two of templated-insertion (TI), which contain a number of potential drivers. An additional mechanism involving hypomethylation of genes at 1q may contribute to the aberrant gene expression of a number of genes. Expression changes associated with whole-arm gains were substantial and gene set enrichment analysis identified metabolic processes, apoptotic resistance, signaling via the MAPK pathway, and upregulation of transcription factors as being key drivers of the adverse prognosis associated with these variants. CONCLUSIONS:Multiple layers of genetic complexity impact the phenotype associated with CNAs on chr1 to generate its associated clinical phenotype. Whole-arm gains of 1q are the critically important prognostic group that deregulate multiple pathways, which may offer therapeutic vulnerabilities.
PMID: 37449980
ISSN: 1557-3265
CID: 5537862

Haplodeficiency of the 9p21 Tumor Suppressor Locus Causes Myeloid Disorders Driven by the Bone Marrow Microenvironment

Feng, Jue; Hsu, Pei-Feng; Esteva, Eduardo; Labella, Rossella; Wang, Yueyang; Khodadadi-Jamayran, Alireza; Pucella, Joseph Nicholas; Liu, Cynthia Z; Arbini, Arnaldo A; Tsirigos, Aristotelis; Kousteni, Stavroula; Reizis, Boris
The chromosome 9p21 locus comprises several tumor suppressor genes including MTAP, CDKN2A and CDKN2B, and its homo- or heterozygous deletion is associated with reduced survival in multiple cancer types. We report that mice with germline monoallelic deletion or induced biallelic deletion of the 9p21-syntenic locus (9p21s) developed a fatal myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN)-like disease associated with aberrant trabecular bone formation and/or fibrosis in the bone marrow (BM). Reciprocal BM transfers and conditional targeting of 9p21s suggested that the disease originates in the BM stroma. Single-cell analysis of 9p21s-deficient BM stroma revealed the expansion of chondrocyte and osteogenic precursors, reflected in increased osteogenic differentiation in vitro. It also showed reduced expression of factors maintaining hematopoietic stem/progenitor cells, including Cxcl12. Accordingly, 9p21s-deficient mice showed reduced levels of circulating Cxcl12 and concomitant upregulation of the pro-fibrotic chemokine Cxcl13 and osteogenesis- and fibrosis-related multifunctional glycoprotein Osteopontin (OPN)/Spp1. Our study highlights the potential of mutations in the BM microenvironment to drive MDS/MPN-like disease.
PMID: 37267505
ISSN: 1528-0020
CID: 5543492

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