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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

Epstein-Barr Virus-Positive Primary Central Nervous System Lymphoma in a 40-Year-Old Immunocompetent Patient [Case Report]

Hajtovic, Sabastian; Liu, Cynthia; Diefenbach, Catherine M; Placantonakis, Dimitris G
Epstein-Barr virus-positive (EBV+) primary central nervous system lymphoma (PCNSL) is a clinical entity rarely reported in young immunocompetent patients. Here, we present the case of a 40-year-old female with no history of immunosuppression or immunodeficiency, who presented with a ring-enhancing lesion in the right basal ganglia. The tumor generated significant vasogenic edema and mass effect, causing midline shift, symptoms of increased intracranial pressure, and rapidly progressive neurologic dysfunction. She underwent gross total resection of the tumor through a tubular retractor. Her tumor was of the diffuse large B cell lymphoma (DLBCL) subtype of PCNSL and was positive for EBV. No immunodeficiency or extracranial disease was identified. After adjuvant therapy with high-dose methotrexate, rituximab, and temozolomide, she remains disease-free two years after initial presentation. EBV+ PCNSL, although rare in young immunocompetent adults, poses unique clinical challenges and may require surgical intervention in the acute setting in some cases.
PMCID:7886623
PMID: 33614348
ISSN: 2168-8184
CID: 5091932

Human T cell lymphotropic virus type-1 associated lymphoma presenting as an intramuscular mass of the calf

Gorelik, Natalia; T Hoda, Syed; Petchprapa, Catherine; Liu, Cynthia; Adler, Ronald
Adult T cell leukemia/lymphoma (ATLL) is a mature T cell neoplasm caused by the human oncogenic retrovirus human T lymphotropic virus type-1 (HTLV-1). While several musculoskeletal manifestations have been described in ATLL, skeletal muscle involvement is unusual, with only four cases reported in the English-language literature. We present a rare case of ATLL manifesting as an intra-muscular calf mass in a 58-year-old man who immigrated to the USA from West Africa. While skeletal muscle involvement by lymphoma is uncommon, it remains important to consider within the differential diagnosis when there are suggestive imaging findings because it entails important technical biopsy considerations as well as treatment implications. This case report also raises awareness of ATLL presenting outside of typical HTLV-1 endemic areas, related to current population migration patterns. ATLL should therefore be considered in patients with appropriate risk factors.
PMID: 32076761
ISSN: 1432-2161
CID: 4313262

Non-Hodgkin Lymphoma with Synovial Involvement of the Knee

Kim, Brandon; Raphael, Bruce; Liu, Cynthia; Golden, Brian D
Musculoskeletal involvement occurs in approximately 25% of patients diagnosed with non-Hodgkin lymphoma (NHL). Skeletal involvement is typically secondary, with primary lymphoma of the bone being much rarer. We describe a case in which a 52-year-old man initially presented features suggestive of Lyme arthritis in his left knee. A synovial biopsy performed as part of a synovectomy procedure revealed a proliferative synovium with dense lymphoplasmacytic B cell infiltrate, suggestive of NHL. An inguinal lymph node biopsy was also performed but did not produce results pathologically similar to those of the left knee synovial biopsy.
PMID: 31785142
ISSN: 2328-5273
CID: 4249752

Mantle Cell Lymphoma With Mantle Zone Growth Pattern

Yuan, Ji; Li, Shaoying; Liu, Xin; Su, Ruijun Jeanna; Chen, Mingyi; Wu, Xiaojun; Zheng, Gang; Smith, Lynette M; Wang, Lifu; Li, Yanxia; Liu, Cynthia; Zhou, Jiehao; Shen, Qi; Zhang, Linsheng; Wang, Endi; Xu, Mina L; Pan, Zenggang
OBJECTIVES/OBJECTIVE:To characterize the clinical and pathologic features of mantle cell lymphoma with mantle zone growth pattern (MCL-MZGP). METHODS:The clinicopathologic data from 35 cases of MCL-MZGP obtained in 12 centers were analyzed. RESULTS:The patients with MCL-MZGP typically sought treatment at high clinical stages (81%). Intriguingly, 40% (14/35) of cases were incidentally noted. The lymph nodes with MCL-MZGP showed preserved architecture and expanded mantles containing lymphoma cells with classic or small cell cytology. MCL-MZGP was positive for BCL2 (96%, bright), CD5 (82%, moderate), cyclin D1 (100%), and SOX11 (89%). Clinically, our study revealed no significant difference in the overall survival between patients managed with observation alone and those who received chemotherapy. CONCLUSIONS:MCL-MZGP was often incidentally identified and resembled reactive mantles. Therefore, recognition of this unusual morphology emphasizes the utility of cyclin D1 immunostain in the cases with suspicious morphology. However, the clinical significance of these findings is still unclear.
PMID: 31140550
ISSN: 1943-7722
CID: 3957922

CD36 Is a Leukemia Stem Cell Chemoresistance Gene and Confers an Adverse Prognosis in Acute Myeloid Leukemia [Meeting Abstract]

Gonzalez, Monica del Rey; Habeeb, Omar; Stranahan, Alec; Hu, Wenhou; Devlin, Sean; Liu, Cynthia; Arbini, Arnaldo; Park, Christopher
ISI:000478081102284
ISSN: 0023-6837
CID: 4047692

Novel Multi-Parameter Flow Cytometry Approaches and Data Analysis Tools for the Evaluation and Detection of Leukemia Stem Cells [Meeting Abstract]

Srinivasan, Kritika; Bhaskar, Anurag; Alexandre, Jason; Winters, Aidan; Zhang, Emily; Akker, Yelena; Liu, Cynthia; Arbini, Arnaldo; Chattopadhyay, Pratip; Park, Christopher
ISI:000478081102402
ISSN: 0023-6837
CID: 4047702

CD36 Is a Leukemia Stem Cell Chemoresistance Gene and Confers an Adverse Prognosis in Acute Myeloid Leukemia [Meeting Abstract]

Gonzalez, Monica del Rey; Habeeb, Omar; Stranahan, Alec; Hu, Wenhou; Devlin, Sean; Liu, Cynthia; Arbini, Arnaldo; Park, Christopher
ISI:000478915501043
ISSN: 0893-3952
CID: 4048112

Novel Multi-Parameter Flow Cytometry Approaches and Data Analysis Tools for the Evaluation and Detection of Leukemia Stem Cells [Meeting Abstract]

Srinivasan, Kritika; Bhaskar, Anurag; Alexandre, Jason; Winters, Aidan; Zhang, Emily; Akker, Yelena; Liu, Cynthia; Arbini, Arnaldo; Chattopadhyay, Pratip; Park, Christopher
ISI:000478915501161
ISSN: 0893-3952
CID: 4048122

STIM1 and STIM2 Mediate Cancer-Induced Inflammation in T Cell Acute Lymphoblastic Leukemia

Saint Fleur-Lominy, Shella; Maus, Mate; Vaeth, Martin; Lange, Ingo; Zee, Isabelle; Suh, David; Liu, Cynthia; Wu, Xiaojun; Tikhonova, Anastasia; Aifantis, Iannis; Feske, Stefan
T cell acute lymphoblastic leukemia (T-ALL) is commonly associated with activating mutations in the NOTCH1 pathway. Recent reports have shown a link between NOTCH1 signaling and intracellular Ca2+ homeostasis in T-ALL. Here, we investigate the role of store-operated Ca2+ entry (SOCE) mediated by the Ca2+ channel ORAI1 and its activators STIM1 and STIM2 in T-ALL. Deletion of STIM1 and STIM2 in leukemic cells abolishes SOCE and significantly prolongs the survival of mice in a NOTCH1-dependent model of T-ALL. The survival advantage is unrelated to the leukemic cell burden but is associated with the SOCE-dependent ability of malignant T lymphoblasts to cause inflammation in leukemia-infiltrated organs. Mice with STIM1/STIM2-deficient T-ALL show a markedly reduced necroinflammatory response in leukemia-infiltrated organs and downregulation of signaling pathways previously linked to cancer-induced inflammation. Our study shows that leukemic T lymphoblasts cause inflammation of leukemia-infiltrated organs that is dependent on SOCE.
PMID: 30208327
ISSN: 2211-1247
CID: 3277772