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Carlos Murga-Zamalloa, Megan S Lim Department of Pathology, University of Michigan, Ann Arbor, MI, USA Abstract: Receptor tyrosine kinases have emerged as promising therapeutic targets for a diverse set of tumors. Overactivation of the tyrosine kinase anaplastic lymphoma kinase (ALK) has been reported in several types of malignancies such as anaplastic large cell lymphoma, inflammatory myofibroblastic tumor, neuroblastoma, and non-small-cell lung carcinoma. Further characterization of the molecular role of ALK has revealed an oncogenic signaling signature that results in tumor dependence on ALK. ALK-positive tumors display a different behavior than their ALK-negative counterparts; however, the specific role of ALK in some of these tumors remains to be elucidated. Although more studies are required to establish selective targeting of ALK as a definitive therapeutic option, initial trials have shown extraordinary results in the majority of cases. Keywords: lymphoma, therapy, kinase, pathobiology

Abstract: Richter syndrome (RS) describes a phenomenon in which a patient with chronic lymphocytic leukemia (CLL) develops an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). Reports of cutaneous RS remain exceedingly rare. We report a 61-year-old woman with relapsed/refractory CLL presenting with several subcutaneous nodules on her arms and legs and a single dermal plaque on her abdomen. Skin biopsy revealed a diagnosis of DLBCL, ABC-type, and her clinical status rapidly deteriorated following diagnosis. We review the variety of clinical presentations of cutaneous RS, its association with CLL, risk factors for RS development in CLL patients, and the distinctive histopathologic and immunophenotypic features of DLBCL. We hope to highlight the importance of prompt skin biopsy in patients with CLL presenting with progressive skin lesions and increase awareness of this aggressive clinical syndrome., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Because of its low frequency in adult populations and clinical and laboratory overlap with hemophagocytic lymphohistiocytosis and other T-cell lymphomas, T-cell/natural killer (NK) cell systemic, chronic, active Epstein-Barr virus (EBV) (T/NK sCAEBV) infection remains underdiagnosed, preventing critical, prompt therapeutic interventions., Methods: We report a 5-case series that included 2 adult patients with T/NK sCAEBV and 3 additional adult patients with T/NK lymphomas with concomitant systemic EBV infection to review these entities' overlapping diagnostic and clinical features., Results: Approximately 95% of the world population has been infected with EBV during their lifetime, and infection is usually asymptomatic, with symptomatic cases eventually resolving spontaneously. A small subset of immunocompetent patients develops CAEBV, a life-threatening complication resulting from EBV-infected T-cell or NK cell neoplastic lymphocytes. The sites of end-organ damage in T/NK sCAEBV demonstrate pathologic findings such as reactive lymphoid proliferations, making the diagnosis difficult to establish, with the only curative option being an allogeneic hematopoietic stem cell transplant., Conclusions: This diagnosis is most prevalent in Asia, with few cases reported in Western countries. Adult age is an independent risk factor for poor outcomes, and most cases are diagnosed in pediatric populations., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Purpose: Many peripheral and cutaneous T-cell lymphoma (CTCL) subtypes are poorly responsive to conventional chemotherapeutic agents and associated with dismal outcomes. The zinc finger transcription factor GATA-3 and the transcriptional program it instigates are oncogenic and highly expressed in various T-cell neoplasms. Posttranslational acetylation regulates GATA-3 DNA binding and target gene expression. Given the widespread use of histone deacetylase inhibitors (HDACi) in relapsed/refractory CTCL, we sought to examine the extent to which these agents attenuate the transcriptional landscape in these lymphomas., Experimental Design: Integrated GATA-3 chromatin immunoprecipitation sequencing and RNA sequencing analyses were performed in complementary cell line models and primary CTCL specimens treated with clinically available HDACi., Results: We observed that exposure to clinically available HDACi led to significant transcriptional reprogramming and increased GATA-3 acetylation. HDACi-dependent GATA-3 acetylation significantly impaired both its ability to bind DNA and transcriptionally regulate its target genes, thus leading to significant transcriptional reprogramming in HDACi-treated CTCL., Conclusions: Beyond shedding new light on the mechanism of action associated with HDACi in CTCL, these findings have significant implications for their use, both as single agents and in combination with other novel agents, in GATA-3-driven lymphoproliferative neoplasms., (©2024 American Association for Cancer Research.)

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare and relatively indolent B-cell lymphoma. Characteristically, the [lymphocyte-predominant (LP)] tumor cells are embedded in a microenvironment enriched in lymphocytes. More aggressive variants of mature B-cell and peripheral T-cell lymphomas exhibit nuclear expression of the polo-like kinase 1 (PLK1) protein, stabilizing MYC (alias c-myc) and associated with worse clinical outcomes. This study demonstrated expression of PLK1 in the LP cells in 100% of NLPHL cases (n = 76). In contrast, <5% of classic Hodgkin lymphoma cases (n = 70) showed PLK1 expression within the tumor cells. Loss-of-function approaches demonstrated that the expression of PLK1 promoted cell proliferation and increased MYC stability in NLPHL cell lines. Correlation with clinical parameters revealed that the increased expression of PLK1 was associated with advanced-stage disease in patients with NLPHL. A multiplex immunofluorescence panel coupled with artificial intelligence algorithms was used to correlate the composition of the tumor microenvironment with the proliferative stage of LP cells. The results showed that LP cells with PLK1 (high) expression were associated with increased numbers of cytotoxic and T-regulatory T cells. Overall, the findings demonstrate that PLK1 signaling increases NLPHL proliferation and constitutes a potential vulnerability that can be targeted with PLK1 inhibitors. An active immune surveillance program in NLPHL may be a critical mechanism limiting PLK1-dependent tumor growth., Competing Interests: Disclosure Statement M.L.X. receives financial support for consultancy at Treeline Biosciences., (Copyright © 2024 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

T-cell lymphomas are aggressive neoplasms characterized by poor responses to current chemotherapeutic agents. Expression of the l-type amino acid transporter 1 (LAT 1, SLC7A5) allows for the expansion of healthy T-cell counterparts, and upregulation of LAT1 has been reported in precursor T-cell acute leukemia. Therefore, the expression of LAT1 was evaluated in a cohort of cutaneous and peripheral T-cell lymphomas. The findings demonstrated that LAT1 is upregulated in aggressive variants and absent in low-grade or indolent disease such as mycosis fungoides. In addition, upregulated LAT1 expression was seen in a large proportion of aggressive peripheral T-cell lymphomas, including peripheral T-cell lymphoma not otherwise specific (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL). The anti-tumor effects of two novel non-cleavable and bifunctional compounds, QBS10072S and QBS10096S, that combine a potent cytotoxic chemotherapeutic domain (tertiary N-bis(2-chloroethyl)amine) with the structural features of a selective LAT1 substrate (aromatic β-amino acid) were tested in vitro and in vivo in T-cell lymphoma cell lines. The findings demonstrated decreased survival of T-cell lymphoma lines with both compounds. Overall, the results demonstrate that LAT1 is a valuable biomarker for aggressive T-cell lymphoma counterparts and QBS10072S and QBS10096S are successful therapeutic options for these aggressive diseases., Competing Interests: This study received funding from Quadriga Biosciences. Inc. At the time of the study, Bernd Jandeleit, Wolf-Nicolas Fischer, and Mirna Rodriguez were paid employees of Quadriga Biosciences, Inc. Mirna Rodriguez and Wolf-Nicholas Fisher (Quadriga Biosciences) designed and conducted in-vitro cytotoxicity experiments. At the time of the study, Bernd Jandeleit and Wolf-Nicolas Fischer were named inventors on the US patent application Jandeleit, B, et al. Beta-substituted beta-amino acids and analogs as chemotherapeutic agents and uses thereof. US patent publication US 9783,487. Guangyao Gao was a paid contractor for Quadriga Biosciences Inc. All authors declare no other competing interests, (© 2023 Published by Elsevier Ltd.)

T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive neoplasm of mature T-cells. Most patients with T-PLL present with lymphocytosis, anemia, thrombocytopenia, and hepatosplenomegaly. Correct identification of T-PLL is essential because treatment for this disease is distinct from that of other T-cell neoplasms. In 2019, the T-PLL International Study Group (TPLL-ISG) established criteria for the diagnosis, staging, and assessment of response to treatment of T-PLL with the goal of harmonizing research efforts and supporting clinical decision-making. T-PLL pathogenesis is commonly driven by T-cell leukemia 1 ( TCL1 ) overexpression and ATM loss, genetic alterations that are incorporated into the TPLL-ISG diagnostic criteria. The cooperativity between TCL1 family members and ATM is seemingly unique to T-PLL across the spectrum of T-cell neoplasms. The role of the T-cell receptor, its downstream kinases, and JAK/STAT signaling are also emerging themes in disease pathogenesis and have obvious therapeutic implications. Despite improved understanding of disease pathogenesis, alemtuzumab remains the frontline therapy in the treatment of naïve patients with indications for treatment given its high response rate. Unfortunately, the responses achieved are rarely durable, and the majority of patients are not candidates for consolidation with hematopoietic stem cell transplantation. Improved understanding of T-PLL pathogenesis has unveiled novel therapeutic vulnerabilities that may change the natural history of this lymphoproliferative neoplasm and will be the focus of this concise review.

The dynamins are a family of ubiquitously expressed GTPase proteins, best known for their role in membrane remodeling. Their contribution to hematopoiesis is incompletely recognized. Individuals with Charcot-Marie-Tooth disease with dynamin-2 (DNM2) mutations often develop neutropenia. We previously reported that dynamin (DNM) inhibition impairs SDF1a-mediated migration in megakaryocytes. Here, we report on conditionally Dnm2 deleted mice in hematopoietic tissues using the Vav-Cre murine strain. Homozygous Dnm2 deletion in blood tissues is embryonic lethal. Dnm2het male mice only developed a slightly decreased hemoglobin level. Dnm2het female mice developed leukopenia by 40 weeks of age and neutropenia by 65 weeks of age. Flow cytometry revealed decreased lineage-negative cells and granulocyte-monocyte progenitors in Dnm2het female mice. Immunohistochemical staining of bone marrow (BM) for mature neutrophils with Ly6G was decreased and myelodysplastic features were present in the BM of Dnm2het female mice. A linear distribution of Ly6G+ BM cells along blood vessels was observed in fewer Dnm2het mice than in controls, suggesting that the migration pattern in the marrow is altered. Marrow neutrophils treated with dynamin inhibitor, dynasore, showed increased cell surface CXCR4, suggesting that abnormal migration results in marrow neutrophil retention. Dnm2het female mice also developed splenomegaly secondary to germinal center hyperplasia at younger ages, suggesting perturbed immunity. In summary, female mice with BM Dnm2 haploinsufficiency developed neutropenia as they aged with decreased granulocyte progenitor production and migration defects. Our studies indicate a potential mechanism for the development of chronic idiopathic neutropenia, a disease that predominantly presents in middle-aged women., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Bisphenol S (BPS) is an endocrine disrupting chemical and the second most abundant bisphenol detected in humans. We have recently demonstrated that in utero exposure to BPS reduces human placenta cell fusion by interfering with epidermal growth factor (EGF)-dependent EGF receptor (EGFR) activation. Our previous work suggests that this occurs via binding of BPS to the extracellular domain of EGFR. However, whether BPS directly binds to EGFR has not been confirmed. We evaluated the binding ability of BPA, BPF and BPS to EGFR to determine whether EGFR binding is a unique attribute of BPS. To test these hypotheses, we first exposed HTR-8/SVneo cells to BPS, BPA, or BPF, with or without EGF. When co-exposed to EGF, BPS, but not BPA nor BPF, reduced EGFR phosphorylation by ∼60%, demonstrating that only BPS can interfere with EGF-dependent EGFR activation. As this indicates that BPS binding to the extracellular domain is responsible for its effect, we performed a computational search for putative binding sites on the EGFR extracellular domain, and performed ligand docking of BPS, BPA, and BPF at these sites. We identified three sites where polar interactions between positively charged residues and the sulfonyl group of BPS could lead binding selectivity over BPA and BPF. To test whether EGFR mutations at the predicted BPS binding sites (Arg255, Lys454, and Arg297) could prevent BPS's interference on EGFR activation, mutations for each EGFR target amino acids (R255A, R297A, and K454A) were introduced. For variants with R297A or K454A mutations, BPS did not affect EGF-mediated EGFR phosphorylation or EGFR-mediated cell invasion, suggesting that these residues are needed for the BPS antagonism effect on EGFR. In conclusion, BPS, but not BPA or BPF, interferes with EGFR-mediated trophoblast cell functions through binding at Arg297 and Lys454 amino acid residues in the extracellular domain of EGFR., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Almudena Veiga-Lopez reports financial support was provided by The National Institutes of Health. Almudena Veiga-Lopez reports a relationship with the National Institute of Environmental Health Sciences of the National Institute of Health that includes: funding grants. The authors declare no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The reciprocal relationship between malignant T cells and lymphoma-associated macrophages (LAM) within the tumor microenvironment (TME) is unique, as LAMs are well poised to provide ligands for antigen, costimulatory, and cytokine receptors that promote T-cell lymphoma growth. Conversely, malignant T cells promote the functional polarization and homeostatic survival of LAM. Therefore, we sought to determine the extent to which LAMs are a therapeutic vulnerability in these lymphomas, and to identify effective therapeutic strategies for their depletion. We utilized complementary genetically engineered mouse models and primary peripheral T-cell lymphoma (PTCL) specimens to quantify LAM expansion and proliferation. A high-throughput screen was performed to identify targeted agents that effectively deplete LAM within the context of PTCL. We observed that LAMs are dominant constituents of the TME in PTCL. Furthermore, their dominance was explained, at least in part, by their proliferation and expansion in response to PTCL-derived cytokines. Importantly, LAMs are a true dependency in these lymphomas, as their depletion significantly impaired PTCL progression. These findings were extrapolated to a large cohort of human PTCL specimens where LAM proliferation was observed. A high-throughput screen demonstrated that PTCL-derived cytokines led to relative resistance to CSF1R selective inhibitors, and culminated in the identification of dual CSF1R/JAK inhibition as a novel therapeutic strategy to deplete LAM in these aggressive lymphomas. Malignant T cells promote the expansion and proliferation of LAM, which are a bone fide dependency in these lymphomas, and are effectively depleted with a dual CSF1R/JAK inhibitor., Significance: LAMs are a therapeutic vulnerability, as their depletion impairs T-cell lymphoma disease progression. Pacritinib, a dual CSF1R/JAK inhibitor, effectively impaired LAM viability and expansion, prolonged survival in preclinical T-cell lymphoma models, and is currently being investigated as a novel therapeutic approach in these lymphomas., Competing Interests: P. Gann reports other from University of Michigan during the conduct of the study. R.A. Wilcox reports grants and non-financial support from Astex, Adagene, Abbvie, AstraZeneca, Corvus Pharmaceuticals, CTI Biopharma; grants from Affimed, Bayer, BeiGene, Epizyme, Genentech, Gilead, MEI Pharma, Merck, and Roche outside the submitted work. No disclosures were reported by the other authors., (© 2022 The Authors; Published by the American Association for Cancer Research.)

Mature T-cell lymphomas represent neoplastic expansions of T-cell lymphocytes with a post-thymic derivation. Most of these tumors feature aggressive clinical behavior and challenging histopathological diagnosis and classification. Novel findings in the genomic landscape of T-cell lymphomas are helping to improve the understanding of the biology and the molecular mechanisms that underly its clinical behavior. The most recent WHO-HAEM5 classification of hematolymphoid tumors introduced novel molecular and histopathological findings that will aid in the diagnostic classification of this group of neoplasms. The current review article summarizes the most relevant diagnostic features of peripheral T-cell lymphomas with an emphasis on the updates that are incorporated at the WHO-HAEM5., Competing Interests: The authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor RW declared a past collaboration with the authors., (Copyright © 2022 Murga-Zamalloa and Inamdar.)

Neoplasms originating from thymic T-cell progenitors and post-thymic mature T-cell subsets account for a minority of lymphoproliferative neoplasms. These T-cell derived neoplasms, while molecularly and genetically heterogeneous, exploit transcription factors and signaling pathways that are critically important in normal T-cell biology, including those implicated in antigen-, costimulatory-, and cytokine-receptor signaling. The transcription factor GATA-3 regulates the growth and proliferation of both immature and mature T cells and has recently been implicated in T-cell neoplasms, including the most common mature T-cell lymphoma observed in much of the Western world. Here we show that GATA-3 is a proto-oncogene across the spectrum of T-cell neoplasms, including those derived from T-cell progenitors and their mature progeny, and further define the transcriptional programs that are GATA-3 dependent, which include therapeutically targetable gene products. The discovery that p300-dependent acetylation regulates GATA-3 mediated transcription by attenuating DNA binding has novel therapeutic implications. As most patients afflicted with GATA-3 driven T-cell neoplasms will succumb to their disease within a few years of diagnosis, these findings suggest opportunities to improve outcomes for these patients., (© 2022. The Author(s).)

Peripheral T-cell lymphomas (PTCL) are agressive lymphomas that develop from mature T cells. The most common PTCLs are genetically, molecularly, and clinically diverse and are generally associated with dismal outcomes. While Notch signaling plays a critically important role in both the development of immature T cells and their malignant transformation, its role in PTCL is poorly understood, despite the increasingly appreciated function of Notch in regulating the proliferation and differentiation of mature T cells. Here, we demonstrate that Notch receptors and their Delta-like family ligands (DLL1/DLL4) play a pathogenic role in PTCL. Notch1 activation was observed in common PTCL subtypes, including PTCL-not otherwise specified (NOS). In a large cohort of PTCL-NOS biopsies, Notch1 activation was significantly associated with surrogate markers of proliferation. Complementary genetically engineered mouse models and spontaneous PTCL models were used to functionally examine the role of Notch signaling, and Notch1/Notch2 blockade and pan-Notch blockade using dominant-negative MAML significantly impaired the proliferation of malignant T cells and PTCL progression in these models. Treatment with DLL1/DLL4 blocking antibodies established that Notch signaling is ligand-dependent. Together, these findings reveal a role for ligand-dependent Notch signaling in driving peripheral T-cell lymphomagenesis., Significance: This work demonstrates that ligand-dependent Notch activation promotes the growth and proliferation of mature T-cell lymphomas, providing new therapeutic strategies for this group of aggressive lymphomas., (©2022 American Association for Cancer Research.)

Background: Primary intestinal T-cell lymphomas are uncommon malignancies that pose a diagnostic dilemma, because the clinical features and imaging findings commonly overlap with those encountered in inflammatory bowel diseases., Case Presentation: The current clinical case report describes the clinical history, laboratory findings and histopathological analysis from a patient with non-specific gastrointestinal symptoms with a presumptive clinical diagnosis of inflammatory bowel disease, and two intestinal biopsy specimens with non-specific findings. Due to the persistent symptoms a third biopsy was consistent with primary intestinal T-cell lymphoma, a diagnosis that was elusive for months after the initial presentation. Clinical correlation with laboratory and histopathological findings is required to establish a definitive diagnosis and to further stratify the patients. In addition, the neoplastic cells featured partial expression of CD30, which had relevant therapeutic implications., Conclusions: Suspicion for an intestinal T-cell lymphoproliferative disorder should always exist in patients with persistent abdominal symptoms with no clear etiology. The current discussion provides a summary and review of the key diagnostic histological features for the classification of primary intestinal T-cell lymphomas. In addition, the discussion describes how specific the histological findings are relevant for the clinical management decisions., (© 2022. The Author(s).)

Myeloid sarcomas can be detected in up to 30% of acute myeloid leukemia cases or occur de-novo without bone marrow involvement. The most frequent localization of myeloid sarcomas in the abdominal cavity is the small intestine, and gastric presentations are infrequent, frequently misdiagnosed, and a high level of suspicion should exist when the characteristic histomorphology features are present. The current review features a case report with gastric presentation of myeloid sarcoma in a patient with a diagnosis of acute myeloid leukemia with trisomy 8. In addition, a review of the literature of intestinal-type myeloid sarcomas shows that less than 15% of these cases have been reported in the stomach. The most common molecular aberrancy detected in intestinal myeloid sarcomas is the fusion protein CBFB-MYH11. A review of several large studies demonstrates that the presence of myeloid sarcoma does not constitute an independent prognostic factor. The therapeutic approach will be tailored to the specific genetic abnormalities present, and systemic chemotherapy with hematopoietic stem cell transplant is the most efficient strategy., Competing Interests: Competing interests: The authors declare no conflict of Interest.

Diffuse large B-cell lymphoma featuring overexpression of MYC and B-Cell Lymphoma 2 (double expressor lymphoma, DEL) is associated with poor outcomes. Existing evidence suggesting improved outcomes for DEL with the use of more intensive regimens than R-CHOP is restricted to younger patients and based on limited evidence from low patient numbers. We retrospectively evaluated the impact of intensive frontline regimens versus R-CHOP in a multicenter analysis across 7 academic medical centers in the United States. We collected 90 cases of DEL, 46 out of 90 patients (51%) received R-CHOP and 44/90 (49%) received an intensive regimen, which was predominantly DA-EPOCH-R. Treatment cohorts were evenly balanced for demographics and disease characteristics, though the intensive group had a higher lactate dehydrogenase (LDH, 326 vs. 230 U/L p = 0.06) and presence of B-symptoms (50% vs. 22%, p = 0.01) compared to the R-CHOP cohort. There was no difference in PFS (median 53 vs. 38 months, p = 0.49) or overall survival (67 vs. not reached months, p = 0.14) between the R-CHOP and intensive therapy cohorts, respectively. On multivariate analysis, intensive therapy was associated with a hazard ratio of 2.35 (95% CI 0.74-7.41), though this was not statistically significant. Additionally, a subgroup analysis of intermediate high-risk lymphoma defined by IPI ≥3 did not identify a difference in survival outcomes between regimens. We conclude that in our multi-center cohort there is no evidence supporting the use of intensive regimens over R-CHOP, suggesting that R-CHOP remains the standard of care for treating DEL., (© 2021 John Wiley & Sons Ltd.)

Purpose: Peripheral T-cell lymphomas are clinically aggressive and usually fatal, as few complete or durable remissions are achieved with currently available therapies. Recent evidence supports a critical role for lymphoma-associated macrophages during T-cell lymphoma progression, but the specific signals involved in the cross-talk between malignant T cells and their microenvironment are poorly understood. Colony-stimulator factor 1 receptor (CSF1R, CD115) is required for the homeostatic survival of tissue-resident macrophages. Interestingly, its aberrant expression has been reported in a subset of tumors. In this article, we evaluated its expression and oncogenic role in T-cell lymphomas., Experimental Design: Loss-of-function studies, including pharmacologic inhibition with a clinically available tyrosine kinase inhibitor, pexidartinib, were performed in multiple in vitro and in vivo models. In addition, proteomic and genomic screenings were performed to discover signaling pathways that are activated downstream of CSF1R signaling., Results: We observed that CSF1R is aberrantly expressed in many T-cell lymphomas, including a significant number of peripheral and cutaneous T-cell lymphomas. Colony-stimulating factor 1 (CSF1), in an autocrine or paracrine-dependent manner, leads to CSF1R autophosphorylation and activation in malignant T cells. Furthermore, CSF1R signaling was associated with significant changes in gene expression and in the phosphoproteome, implicating PI3K/AKT/mTOR in CSF1R-mediated T-cell lymphoma growth. We also demonstrated that inhibition of CSF1R in vivo and in vitro models is associated with decreased T-cell lymphoma growth., Conclusions: Collectively, these findings implicate CSF1R in T-cell lymphomagenesis and have significant therapeutic implications., (©2019 American Association for Cancer Research.)

GATA-3 regulates the differentiation, proliferation, survival, and function of peripheral T cells and their thymic progenitors. Recent findings, reviewed here, not only implicate GATA-3 in the pathogenesis of molecularly, genetically, and clinically distinct T-cell lymphoproliferative disorders, but also have significant diagnostic, prognostic, and therapeutic implications., (© 2019 International Union of Biochemistry and Molecular Biology.)

High-risk lymphomas (HRLs) are associated with dismal outcomes and remain a therapeutic challenge. Recurrent genetic and molecular alterations, including c-myc expression and aurora A kinase (AAK) and polo-like kinase-1 (PLK1) activation, promote cell proliferation and contribute to the highly aggressive natural history associated with these lymphoproliferative disorders. In addition to its canonical targets regulating mitosis, the AAK/PLK1 axis directly regulates noncanonical targets, including c-myc. Recent studies demonstrate that HRLs, including T-cell lymphomas and many highly aggressive B-cell lymphomas, are dependent upon the AAK/PLK1 axis. Therefore, the AAK/PLK1 axis has emerged as an attractive therapeutic target in these lymphomas. In addition to reviewing these recent findings, we summarize the rationale for targeting AAK/PLK1 in high-risk and c-myc-driven lymphoproliferative disorders., (© 2019 by The American Society of Hematology.)

Purpose: Population-based incidence rates of breast cancers that are negative for estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2/ neu (triple-negative breast cancer [TNBC]) are higher among African American (AA) compared with white American (WA) women, and TNBC prevalence is elevated among selected populations of African patients. The extent to which TNBC risk is related to East African versus West African ancestry, and whether these associations extend to expression of other biomarkers, is uncertain., Methods: We used immunohistochemistry to evaluate estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2/ neu, androgen receptor and aldehyde dehydrogenase 1 (ALDH1) expression among WA (n = 153), AA (n = 76), Ethiopian (Eth)/East African (n = 90), and Ghanaian (Gh)/West African (n = 286) patients with breast cancer through an institutional review board-approved international research program., Results: Mean age at diagnosis was 43, 49, 60, and 57 years for the Eth, Gh, AA, and WA patients, respectively. TNBC frequency was higher for AA and Gh patients (41% and 54%, respectively) compared with WA and Eth patients (23% and 15%, respectively; P < .001) Frequency of ALDH1 positivity was higher for AA and Gh patients (32% and 36%, respectively) compared with WA and Eth patients (23% and 17%, respectively; P = .007). Significant differences were observed for distribution of androgen receptor positivity: 71%, 55%, 42%, and 50% for the WA, AA, Gh, and Eth patients, respectively ( P = .008)., Conclusion: Extent of African ancestry seems to be associated with particular breast cancer phenotypes. West African ancestry correlates with increased risk of TNBC and breast cancers that are positive for ALDH1.

Survival following anthracycline-based chemotherapy remains poor among patients with most T-cell lymphoproliferative disorders. This may be attributed, at least in part, to cell-autonomous mechanisms of chemotherapy resistance observed in these lymphomas, including the loss of important tumor suppressors and the activation of signaling cascades that culminate in the expression and activation of transcription factors promoting cell growth and survival. Therefore, the identification of novel therapeutic targets is needed. In an effort to identify novel tumor dependencies, we performed a loss-of-function screen targeting ≈500 kinases and identified polo-like kinase 1 (PLK-1). This kinase has been implicated in the molecular cross-talk with important oncogenes, including c-Myc, which is itself an attractive therapeutic target in subsets of T-cell lymphomas and in high-grade ("double hit") diffuse large B-cell lymphomas. We demonstrate that PLK-1 expression is prevalent among these aggressive lymphomas and associated with c-myc expression. Importantly, PLK-1 inhibtion with the PLK-1 inhibitor volasertib significantly reduced downstream c-myc phosphorylation and impaired BRD4 binding to the c-myc gene, thus inhibiting c-myc transcription. Therefore, volasertib led to a nearly complete loss of c-myc expression in cell lines and tumor xenografts, induced apoptosis, and thus warrants further investigation in these aggressive lymphomas., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

PKM2 (pyruvate kinase M2), a critical regulator of glycolysis, is phosphorylated by numerous growth factor receptors and oncogenic tyrosine kinases including NPM-ALK which is expressed in a subset of aggressive T-cell non-Hodgkin lymphomas known as anaplastic large cell lymphoma, ALK-positive. Our previous work demonstrated that phosphorylation of Y105-PKM2 by NPM-ALK regulates a major metabolic shift to promote lymphomagenesis. In addition to its role in metabolism, recent studies have shown that PKM2 promotes oncogenesis by phosphorylating nuclear STAT3 (signal transducer and activator of transcription 3) and regulating transcription of genes involved in cell survival and proliferation. We hypothesized that identification of novel PKM2 interactors could provide additional insights into its expanding functional role in cancer. To this end, immunocomplexes of FLAG-tagged PKM2 were isolated from NPM-ALK-positive ALCL (anaplastic large cell lymphoma) cells and subjected to liquid chromatography tandem mass spectrometry (LC-MS/MS) which led to the identification of polypyrimidine tract-binding protein (PTBP1) as a novel interactor of PKM2. The interaction between PTBP1 and PKM2 was restricted to the nucleus and was dependent on NPM-ALK mediated Y105 phosphorylation of PKM2. Stable shRNA-mediated silencing of PTBP1 resulted in a marked decrease in pY105-PKM2 and pY705-STAT3 which led to decreased ALCL cell proliferation and colony formation. Overall, our data demonstrate that PTBP1 interacts with PKM2 and promotes ALCL oncogenesis by facilitating PKM2-dependent activation of STAT3 within the nucleus.

Purpose: T-cell lymphomas are a molecularly heterogeneous group of non-Hodgkin lymphomas (NHL) that account for a disproportionate number of NHL disease-related deaths due to their inherent and acquired resistance to standard multiagent chemotherapy regimens. Despite their molecular heterogeneity and frequent loss of various T cell-specific receptors, the T-cell antigen receptor is retained in the majority of these lymphomas. As T-cell receptor (TCR) engagement activates a number of signaling pathways and transcription factors that regulate T-cell growth and survival, we examined the TCR's role in mediating resistance to chemotherapy. Experimental Design: Genetic and pharmacologic strategies were utilized to determine the contribution of tyrosine kinases and transcription factors activated in conventional T cells following TCR engagement in acquired chemotherapy resistance in primary T-cell lymphoma cells and patient-derived cell lines. Results: Here, we report that TCR signaling activates a signaling axis that includes ITK, NF-κB, and GATA-3 and promotes chemotherapy resistance. Conclusions: These observations have significant therapeutic implications, as pharmacologic inhibition of ITK prevented the activation of this signaling axis and overcame chemotherapy resistance. Clin Cancer Res; 23(10); 2506-15. ©2016 AACR ., (©2016 American Association for Cancer Research.)

Background: Angioscopy - or endovascular endoscopy - is a catheter-based technique employing a flexible fiberoptic angioscope to directly visualize arterial lumen. Poor resolution and excessive stiffness of pre-existent angioscopes limited their use clinically. Recent advances resulted in novel fused optical fiber bundle angioscopes with improved flexibility and imaging resolution. Use of these devices in endovascular neurosurgery is still largely unexplored., Objective: To evaluate image quality and feasibility of optical angioscopes for diagnostic and interventional neuro-angioscopy in carotid arteries of human cadavers., Methods: A 5-F optical angioscope was used in human cadaveric carotid arteries to inspect integrity of arterial walls, identify atherosclerotic plaques and associated lesions prone to thrombogenicity, place intravascular occlusion coils, and deploy endovascular stents with real-time visualization., Results: Angioscopy provided key information about endoluminal anatomy such as presence and characteristics of atherosclerotic plaques and thrombogenic lesions not detected by conventional diagnostic methods. Direct real-time visualization of vascular lumen during endovascular interventions provided information on spatial distribution of coils, coil loop herniation, and apposition of stent cells against carotid artery wall complementary to angiography., Conclusions: Fused optical fiber bundle angioscopes provide good-quality endoluminal images in human carotid arteries. Their use can feasibly assist in navigation of extracranial carotid arteries to inspect integrity of the arterial wall and identify atherosclerotic plaques and associated lesions vulnerable to thrombogenicity, allow placement of intravascular occlusion coils, and assess apposition of stents to vessel wall. Further in Vivo validation needs to be conducted along with additional research to improve image quality, flexibility, and size of angioscopes., (Copyright © 2016 by the Congress of Neurological Surgeons)

The complex nature of atherosclerosis demands high-resolution approaches to identify subtle thrombogenic lesions and define the risk of plaque rupture. Here, we report the proof-of-concept use of a multimodal scanning fiber endoscope (SFE) consisting of a single optical fiber scanned by a piezoelectric drive that illuminates tissue with red, blue, and green laser beams, and digitally reconstructs images at 30 Hz with high resolution and large fields-of-view. By combining laser-induced reflectance and fluorescence emission of intrinsic fluorescent constituents in arterial tissues, the SFE allowed us to co-generate endoscopic videos with a label-free biochemical map to derive a morphological and spectral classifier capable of discriminating early, intermediate, advanced, and complicated atherosclerotic plaques. We demonstrate the capability of scanning fiber angioscopy for the molecular imaging of vulnerable atherosclerosis by targeting proteolytic activity with a fluorescent probe activated by matrix metalloproteinases. We also show that the SFE generates high-quality spectral images in vivo in an animal model with medium-sized arteries. Multimodal laser-based angioscopy could become a platform for the diagnosis, prognosis, and image-guided therapy of atherosclerosis., Competing Interests: COMPETING FINANCIAL INTERESTS E.S. participates in royalty sharing with his employer, the University of Washington, which has ownership of patents that may gain or lose financially through this publication. The remaining authors declare no competing financial interests.

Inverted sinonasal papilloma (ISP) is a locally aggressive neoplasm associated with sinonasal squamous cell carcinoma (SNSCC) in 10% to 25% of cases. To date, no recurrent mutations have been identified in ISP or SNSCC. Using targeted next-generation sequencing and Sanger sequencing, we identified activating EGFR mutations in 88% of ISP and 77% of ISP-associated SNSCC. Identical EGFR genotypes were found in matched pairs of ISP and associated SNSCC, providing the first genetic evidence of a biologic link between these tumors. EGFR mutations were not identified in exophytic or oncocytic papillomas or non-ISP-associated SNSCC, suggesting that the ISP/SNSCC spectrum is biologically distinct among sinonasal squamous tumors. Patients with ISP harboring EGFR mutations also exhibited an increased progression-free survival compared with those with wild-type EGFR. Finally, treatment of ISP-associated carcinoma cells with irreversible EGFR inhibitors resulted in inactivation of EGFR signaling and growth inhibition. These findings implicate a prominent role for activating EGFR mutations in the pathogenesis of ISP and associated SNSCC and rationalize consideration of irreversible EGFR inhibitors in the therapy of these tumors., (©2015 American Association for Cancer Research.)

The mechanisms underlying the pathogenesis of the constitutively active tyrosine kinase nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) expressing anaplastic large cell lymphoma are not completely understood. Here we show using an integrated phosphoproteomic and metabolomic strategy that NPM-ALK induces a metabolic shift toward aerobic glycolysis, increased lactate production, and biomass production. The metabolic shift is mediated through the anaplastic lymphoma kinase (ALK) phosphorylation of the tumor-specific isoform of pyruvate kinase (PKM2) at Y105, resulting in decreased enzymatic activity. Small molecule activation of PKM2 or expression of Y105F PKM2 mutant leads to reversal of the metabolic switch with increased oxidative phosphorylation and reduced lactate production coincident with increased cell death, decreased colony formation, and reduced tumor growth in an in vivo xenograft model. This study provides comprehensive profiling of the phosphoproteomic and metabolomic consequences of NPM-ALK expression and reveals a novel role of ALK in the regulation of multiple components of cellular metabolism. Our studies show that PKM2 is a novel substrate of ALK and plays a critical role in mediating the metabolic shift toward biomass production and tumorigenesis.

Cilia are highly specialized microtubule-based organelles that have pivotal roles in numerous biological processes, including transducing sensory signals. Defects in cilia biogenesis and transport cause pleiotropic human ciliopathies. Mutations in over 30 different genes can lead to cilia defects, and complex interactions exist among ciliopathy-associated proteins. Mutations of the centrosomal protein 290 kDa (CEP290) lead to distinct clinical manifestations, including Leber congenital amaurosis (LCA), a hereditary cause of blindness due to photoreceptor degeneration. Mice homozygous for a mutant Cep290 allele (Cep290rd16 mice) exhibit LCA-like early-onset retinal degeneration that is caused by an in-frame deletion in the CEP290 protein. Here, we show that the domain deleted in the protein encoded by the Cep290rd16 allele directly interacts with another ciliopathy protein, MKKS. MKKS mutations identified in patients with the ciliopathy Bardet-Biedl syndrome disrupted this interaction. In zebrafish embryos, combined subminimal knockdown of mkks and cep290 produced sensory defects in the eye and inner ear. Intriguingly, combinations of Cep290rd16 and Mkksko alleles in mice led to improved ciliogenesis and sensory functions compared with those of either mutant alone. We propose that altered association of CEP290 and MKKS affects the integrity of multiprotein complexes at the cilia transition zone and basal body. Amelioration of the sensory phenotypes caused by specific mutations in one protein by removal of an interacting domain/protein suggests a possible novel approach for treating human ciliopathies.

Supv3L1 is an evolutionarily conserved helicase that plays a critical role in the mitochondrial RNA surveillance and degradation machinery. Conditional ablation of Supv3L1 in adult mice leads to premature aging phenotypes including loss of muscle mass and adipose tissue and severe skin abnormalities. To get insights into the spatial and temporal expression of Supv3L1 in the mouse, we generated knock-in and transgenic strains in which an EGFP reporter was placed under control of the Supv3L1 native promoter. During development, expression of Supv3L1 begins at the blastocyst stage, becomes widespread and strong in all fetal tissues and cell types, and continues during postnatal growth. In mature animals reporter expression is only slightly diminished in most tissues and continues to be highly expressed in the brain, peripheral sensory organs, and testis. Together, these data confirm that Supv3L1 is an important developmentally regulated gene, which continues to be expressed in all mature tissues, particularly the rapidly proliferating cells of testes, but also in the brain and sensory organs. The transgenic mice and cell lines derived from them constitute a valuable tool for the examination of the spatial and temporal aspects of Supv3L1 promoter activity, and should facilitate future screens for small molecules that regulate Supv3L1 expression.

Mutations in Retinitis Pigmentosa GTPase Regulator (RPGR) are a frequent cause of X-linked Retinitis Pigmentosa (XLRP). The RPGR gene undergoes extensive alternative splicing and encodes for distinct protein isoforms in the retina. Extensive studies using isoform-specific antibodies and mouse mutants have revealed that RPGR predominantly localizes to the transition zone to primary cilia and associates with selected ciliary and microtubule-associated assemblies in photoreceptors. In this chapter, we have summarized recent advances on understanding the role of RPGR in photoreceptor protein trafficking. We also provide new evidence that suggests the existence of discrete RPGR multiprotein complexes in photoreceptors. Piecing together the RPGR-interactome in different subcellular compartments should provide critical insights into the role of alternative RPGR isoforms in associated orphan and syndromic retinal degenerative diseases.

In order to identify new markers around the glaucoma locus GLC1B as a tool to refine its critical region at 2p11.2-2q11.2, we searched the critical region sequence obtained from the UCSC database for tetranucleotide (GATA)n and (GTCT)n repeats of at least 10 units in length. Three out of four potential microsatellite loci were found to be polymorphic, heterozygosity ranging from 64.56% to 79.59%. The identified markers are useful not only for GLC1B locus but also for the study of other disease loci at 2p11.2-2q11.2, a region with scarcity of microsatellite markers.