[Show abstract][Hide abstract] ABSTRACT: The type I insulin-like growth factor receptor (IGF-IR) tyrosine kinase promotes the survival of an aggressive subtype of T-cell lymphoma by interacting with nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) oncogenic protein. NPM-ALK(+) T-cell lymphoma exhibits much higher levels of IGF-IR than normal human T lymphocytes. The mechanisms underlying increased expression of IGF-IR in this lymphoma are not known. We hypothesized that upregulation of IGF-IR could be attributed to previously unrecognized defects that inherently exist in the transcriptional machinery in NPM-ALK(+) T-cell lymphoma.
Screening studies showed substantially lower levels of the transcription factors Ikaros isoform 1 (Ik-1) and myeloid zinc finger 1 (MZF1) in NPM-ALK(+) T-cell lymphoma cell lines and primary tumor tissues from patients than in human T lymphocytes. A luciferase assay supported that Ik-1 and MZF1 suppress IGF-IR gene promoter. Furthermore, ChIP assay showed that these transcription factors bind specific sites located within the IGF-IR gene promoter. Forced expression of Ik-1 or MZF1 in the lymphoma cells decreased IGF-IR mRNA and protein. This decrease was associated with downregulation of pIGF-IR, and the phosphorylation of its interacting proteins IRS-1, AKT, and NPM-ALK. In addition, overexpression of Ik-1 and MZF1 decreased the viability, proliferation, migration, and anchorage-independent colony formation of the lymphoma cells.
Our results provide novel evidence that the aberrant decreases in Ik-1 and MZF1 contribute significantly to the pathogenesis of NPM-ALK(+) T-cell lymphoma through the upregulation of IGF-IR expression. These findings could be exploited to devise new strategies to eradicate this lymphoma.
Molecular Cancer 12/2015; 14(1):324. DOI:10.1186/s12943-015-0324-2 · 4.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Nucleophosmin-anaplastic lymphoma kinase-expressing (NPM-ALK(+)) T-cell lymphoma is an aggressive form of cancer that commonly affects children and adolescents. The expression of NPM-ALK chimeric oncogene results from the chromosomal translocation t(2;5)(p23;q35) that causes the fusion of the ALK and NPM genes. This translocation generates the NPM-ALK protein tyrosine kinase that forms the constitutively activated NPM-ALK/NPM-ALK homodimers. In addition, NPM-ALK is structurally associated with wild-type NPM to form NPM/NPM-ALK heterodimers, which can translocate to the nucleus. The mechanisms that sustain the stability of NPM-ALK are not fully understood. SUMOylation is a posttranslational modification that is characterized by the reversible conjugation of small ubiquitin-like modifiers (SUMOs) with target proteins. SUMO competes with ubiquitin for substrate binding and therefore, SUMOylation is believed to protect target proteins from proteasomal degradation. Moreover, SUMOylation contributes to the subcellular distribution of target proteins. Herein, we found that the SUMOylation pathway is deregulated in NPM-ALK(+) T-cell lymphoma cell lines and primary lymphoma tumors from patients. We also identified Lys(24) and Lys(32) within the NPM domain as the sites where NPM-ALK conjugates with SUMO-1 and SUMO-3. Importantly, antagonizing SUMOylation by the SENP1 protease decreased the accumulation of NPM-ALK and suppressed lymphoma cell viability, proliferation, and anchorage-independent colony formation. One possible mechanism for the SENP1-mediated decrease in NPM-ALK levels was the increase in NPM-ALK association with ubiquitin, which facilitates its degradation. Our findings propose a model in which aberrancies in SUMOylation contribute to the pathogenesis of NPM-ALK(+) T-cell lymphoma. Unraveling such pathogenic mechanisms may lead to devising novel strategies to eliminate this aggressive neoplasm.
Neoplasia (New York, N.Y.) 10/2015; 17(9):742-754. DOI:10.1016/j.neo.2015.09.005 · 4.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Nodal marginal zone lymphoma (NMZL) is a B-cell lymphoma that shares morphologic and immunophenotypic features with extranodal and splenic marginal zone lymphomas but lacks extranodal or splenic involvement at presentation. NMZL occurs mostly in adults with no sex predilection, advanced stage (III or IV), frequent relapses, and a high incidence of tumoral genetic abnormalities including trisomies 3 and 18 and gain of 7q. Pediatric NMZL, however, is a rare but distinct variant of NMZL with characteristic features including male predominance, asymptomatic and localized (stage I) disease, low relapse rates with excellent outcomes, and a lower incidence of essentially similar genetic aberrations compared to adult NMZL. Here we describe a unique case of childhood NMZL with unusual clinicopathologic features for the pediatric variant including generalized lymphadenopathy, high-stage disease with persistence after therapy, unusual immunophenotype (CD5, CD23, and BCL6 positive), and unique chromosomal abnormalities including monosomy 20 and add(10)(p11.2).
[Show abstract][Hide abstract] ABSTRACT: Background:
Precursor B acute lymphoblastic leukemia (B-ALL) is the most common cancer in children and overall, has an excellent prognosis. However, the Philadelphia chromosome translocation (Ph+), t(9;22)(q34;q11), is present in a small subset of patients and confers poor outcomes. CD25 (IL-2 receptor alpha chain) expression has been associated with Ph+ B-ALL in adults, but no similar study has been performed in pediatric B-ALL.
A retrospective analysis of 221 consecutive pediatric patients with a diagnosis of B-ALL (blood and/or bone marrow) from 2009 to 2012 was performed to determine an association between Ph+ B-ALL and CD25 expression. A threshold of 25% was used to define positive cases for CD25 expression by flow cytometry.
There were 221 patients with a diagnosis of B-ALL ranging from 2 to 22 years (median, 6 years). Eight (3.6%) B-ALL patients were positive for the Philadelphia chromosome translocation (Ph+ B-ALL) and 213 were negative (Ph-negative B-ALL). CD25 expression was observed in 6 of 8 (75%) Ph+ B-ALL patients and 6 of 213 (2.8%) Ph-negative B-ALL patients. CD25 expression was significantly higher in Ph+ B-ALL compared to Ph-negative B-ALL, with median CD25 expression of 64% (range 0-93%) and 0.1% (range 0-91%), respectively (P ≤ 0.0002). Therefore, CD25 expression as a predictor of Ph+ B-ALL had 75% sensitivity, 97% specificity, 50% positive predictive value and 99% negative predictive value.
CD25 expression is a specific and relatively sensitive marker for the identification of Ph+ B-ALL in the pediatric population.
International journal of clinical and experimental pathology 10/2014; 7(9):6225-30. · 1.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Post-transplantation lymphoproliferative disorder (PTLD) is an infrequent, but serious complication of solid organ and bone marrow transplantations. The vast majority of the cases are of B-cell origin and usually associated with Epstein-Barr virus (EBV) infection. The non-B (T and NK cell) PTLDs account for up to 14% of the PTLD cases in Western countries. We report a case of a 66-year-old man who received an orthotopic heart transplant for cardiomyopathy 7 years prior to presentation. He was referred to our institution with a hypermetabolic solitary right lower lobe lung nodule with an SUV of 9.2 on PET scan. The combined histomorphological and immunohistochemical pattern was most consistent with monomorphic PTLD, peripheral T-cell lymphoma with angioimmunoblastic features. Molecular studies showed clonal T-cell gamma receptor gene rearrangement. Primary pulmonary involvement of T-cell PTLD is extremely rare. This is the third reported case of T-cell PTLD after cardiac transplantation, primarily involving the lung. Further, studies will be required to determine the appropriate treatment and prognosis of this rare entity.
International journal of clinical and experimental pathology 12/2013; 6(12):3009-13. · 1.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: NPM-ALK chimeric oncogene is aberrantly expressed in an aggressive subset of T-cell lymphoma that frequently occurs in children and young adults. The mechanisms underlying the oncogenic effects of NPM-ALK are not completely elucidated. Inducible nitric oxide synthase (iNOS) promotes the survival and maintains the malignant phenotype of cancer cells by generating NO, a highly active free radical. We tested the hypothesis that iNOS is deregulated in NPM-ALK(+) T-cell lymphoma and promotes the survival of this lymphoma. In line with this possibility, an iNOS inhibitor and NO scavenger decreased the viability, adhesion and migration of NPM-ALK(+) T-cell lymphoma cells, and an NO donor reversed these effects. Moreover, the NO donor salvaged the viability of lymphoma cells treated with ALK inhibitors. In further support of an important role of iNOS, we found iNOS protein to be highly expressed in NPM-ALK(+) T-cell lymphoma cell lines and in 79% of primary tumours but not in human T lymphocytes. Although expression of iNOS mRNA was identified in NPM-ALK(+) T-cell lymphoma cell lines and tumours, iNOS mRNA was remarkably elevated in T lymphocytes, suggesting posttranscriptional regulation. Consistently, we found that miR-26a contains potential binding sites and interacts with the 3'-UTR of iNOS. In addition, miR-26a was significantly decreased in NPM-ALK(+) T-cell lymphoma cell lines and tumours compared with T lymphocytes and reactive lymph nodes. Restoration of miR-26a in lymphoma cells abrogated iNOS protein expression and decreased NO production and cell viability, adhesion, and migration. Importantly, the effects of miR-26a were substantially attenuated when the NO donor was simultaneously used to treat lymphoma cells. Our investigation of the mechanisms underlying the decrease in miR-26a in this lymphoma revealed novel evidence that STAT3, a major downstream substrate of NPM-ALK tyrosine kinase activity, suppresses MIR26A1 gene expression.
The Journal of Pathology 05/2013; 230(1). DOI:10.1002/path.4171 · 7.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The Silences of the Archives, the Reknown of the Story.
The Martin Guerre affair has been told many times since Jean de Coras and Guillaume Lesueur published their stories in 1561. It is in many ways a perfect intrigue with uncanny resemblance, persuasive deception and a surprizing end when the two Martin stood face to face, memory to memory, before captivated judges and a guilty feeling Bertrande de Rols. The historian wanted to go beyond the known story in order to discover the world of the heroes. This research led to disappointments and surprizes as documents were discovered concerning the environment of Artigat’s inhabitants and bearing directly on the main characters thanks to notarial contracts. Along the way, study of the works of Coras and Lesueur took a new direction. Coming back to the affair a quarter century later did not result in finding new documents (some are perhaps still buried in Spanish archives), but by going back over her tracks, the historian could only be struck by the silences of the archives that refuse to reveal their secrets and, at the same time, by the possible openings they suggest, by the intuition that almost invisible threads link here and there characters and events.
American Journal Of Pathology 03/2012; 180(5):1772-80. DOI:10.1016/j.ajpath.2012.01.008 · 4.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A 7-year-old girl presented with pain and progressive swelling on the left plantar surface. Biopsy of a 2.5 cm mass showed nests of large round to oval neoplastic cells with abundant amphophilic to clear cytoplasm, prominent nucleoli and high mitotic activity. Occasional cells showed spindled morphology. Infrequent melanin pigment was present. Melanocytic markers (HMB45, S-100) were diffusely positive. A diagnosis of clear cell sarcoma of soft tissue (CCSS) was made, and the mass was re-excised with negative margins. 28 months later, a 1.0 cm pulmonary nodule was identified and wedge excision showed metastatic CCSS. Cytogenetics showed a complex karyotype (unbalanced translocation der(12;14)(q10;q10), additional chromosome 22 material of unknown origin). Although the CCSS translocation t(12;22)(q13;q12) was not identified, EWSR1 gene rearrangement was detected by fluorescence in situ hybridization (FISH). Reverse transcription polymerase chain reaction (RT-PCR) showed an EWS-ATF1 fusion transcript, confirmed by direct sequencing. CCSS requires differentiation from malignant melanoma, because of overlapping clinical presentations, sites of involvement, histomorphology, immunocytochemical profiles and ultrastructure. In many circumstances, definitive diagnosis is only possible with confirmation of the CCSS-defining translocation.