RESUMEN
The prognostic and predictive role of specific gene mutations in Waldenström Macroglobulinemia (WM) is well-ascertained whereas the clinical impact of chromosome aberrations is far less known. Recent work has provided initial evidence for an adverse prognostic impact of some aberrations, such as del(6q), while other studies suggest a possible relationship between some clinical features (e.g. advanced age and/or inflammatory status) and specific cytogenetic abnormalities. To add to the still limited knowledge on WM cytogenetics and its clinical implications, we herein report our experience in a cohort of WM patients across 23 years. Based on our retrospective study, we found that abnormal karyotype was more represented in older patients and maintained a statistically significant independence from other molecular, clinical, and biological features related to WM. The presence and number of cytogenetic aberrations correlated with inferior overall and progression-free survival outcomes regardless of the type of single chromosome aberration. Our data suggests that the role of the altered karyotype deserves to be further clarified especially in elderly WM patients, in whom cytogenetic abnormalities and disease biology appear to be characterized by a higher degree of complexity.
Asunto(s)
Aberraciones Cromosómicas , Macroglobulinemia de Waldenström , Macroglobulinemia de Waldenström/genética , Macroglobulinemia de Waldenström/mortalidad , Macroglobulinemia de Waldenström/diagnóstico , Humanos , Anciano , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Anciano de 80 o más Años , Adulto , Pronóstico , Supervivencia sin Enfermedad , Cariotipo AnormalRESUMEN
Breast Implant-Associated-Anaplastic Large Cell Lymphoma (BIA-ALCL) is a rare T-cell non-Hodgkin lymphoma associated with breast prosthetic implants and represents a diagnostic challenge. The National Comprehensive Cancer Network (NCCN) guidelines, updated in 2024, recommend for diagnosis an integrated work-up that should include cell morphology, CD30 immunohistochemistry (IHC), and flow cytometry (FCM). CD30 IHC, although the test of choice for BIA-ALCL diagnosis, is not pathognomonic, and this supports the recommendation to apply a multidisciplinary approach. A close collaboration between pathologists and laboratory professionals allowed the diagnosis of three BIA-ALCLs, presented as case reports, within a series of 35 patients subjected to periprosthetic effusions aspiration from 2018 to 2023. In one case, rare neoplastic cells were identified by FCM, and this result was essential in leading the anatomopathological picture as indicative of this neoplasm. In fact, the distinction between a lymphomatous infiltrate from reactive cells may be very complex in the cytopathology and IHC setting when neoplastic cells are rare. On the other hand, one limitation of FCM analysis is the need for fresh samples. In this study, we provide evidence that a dedicated fixative allows the maintenance of an unaltered CD30 expression on the cell surface for up to 72 h.
Asunto(s)
Implantación de Mama , Implantes de Mama , Neoplasias de la Mama , Linfoma Anaplásico de Células Grandes , Humanos , Femenino , Implantes de Mama/efectos adversos , Linfoma Anaplásico de Células Grandes/diagnóstico , Linfoma Anaplásico de Células Grandes/etiología , Linfoma Anaplásico de Células Grandes/patología , Citometría de Flujo , Implantación de Mama/efectos adversos , Exudados y Transudados/metabolismo , Neoplasias de la Mama/complicacionesRESUMEN
OBJECTIVE: Autoimmune gastritis (AIG) is an immunomediated disease targeting parietal cells, eventually resulting in oxyntic-restricted atrophy. This long-term follow-up study aimed at elucidating the natural history, histological phenotype(s), and associated cancer risk of patients with AIG consistently tested H. pylori-negative (naïve H. pylori-negative subjects). DESIGN: Two-hundred eleven naïve H. pylori-negative patients (tested by serology, histology, molecular biology) with AIG (F:M=3.15:1; p<0.001) were prospectively followed up with paired biopsies (T1 vs T2; mean follow-up years:7.5 (SD:4.4); median:7). Histology distinguished non-atrophic versus atrophic AIG. Atrophy was further subtyped/scored as non-metaplastic versus metaplastic (pseudopyloric (PPM) and intestinal (IM)). Enterochromaffin-like-cell (ECL) status was categorised as diffuse versus adenomatoid hyperplasia/dysplasia, and type 1 neuroendocrine tumours (Type1-NETs). RESULTS: Over the long-term histological follow-up, AIG consistently featured oxyntic-predominant-mononuclear inflammation. At T1, PPM-score was greater than IM (200/211 vs 160/211, respectively); IM scores increased from T1 to T2 (160/211 to 179/211), with no changes in the PPM prevalence (T1=200/211; T2=201/211). At both T1/T2, the prevalence of OLGA-III-stage was <5%; no Operative Link on Gastritis Assessment (OLGA)-IV-stage occurred. ECL-cell-status progressed from diffuse to adenomatoid hyperplasia/dysplasia (T1=167/14 vs T2=151/25). Type1-NETs (T1=10; T2=11) always coexisted with extensive oxyntic-atrophy, and ECL adenomatoid-hyperplasia/dysplasia. No excess risk of gastric or other malignancies was found over a cumulative follow-up time of 10 541 person years, except for (marginally significant) thyroid cancer (SIR=3.09; 95% CI 1.001 to 7.20). CONCLUSIONS: Oxyntic-restricted inflammation, PPM (more than IM), and ECL-cell hyperplasia/neoplasia are the histological AIG hallmarks. Compared with the general population, corpus-restricted inflammation/atrophy does not increase the GC risk. The excess of GC risk reported in patients with AIG could plausibly result from unrecognised previous/current H. pylori comorbidity.
Asunto(s)
Gastritis Atrófica , Gastritis , Infecciones por Helicobacter , Helicobacter pylori , Lesiones Precancerosas , Neoplasias Gástricas , Humanos , Hiperplasia , Estudios de Seguimiento , Gastritis/patología , Gastritis Atrófica/epidemiología , Atrofia/complicaciones , Lesiones Precancerosas/patología , Inflamación/complicaciones , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/patología , Metaplasia , Neoplasias Gástricas/complicacionesRESUMEN
Accessory spleens (AcS) may play a relevant role in immune thrombocytopenia (ITP) and possibly contribute to ITP relapse following splenectomy. Little is known about the immune microenvironment of AcS in ITP. To address this issue, we compared the histological features of eight matched AcS and main spleen (MS) samples, obtained from adult patients with primary ITP. AcS and MS had overlapping immune architectural features and lymphoid composition, suggesting that similar immunologic events occur in AcS and MS of ITP. These findings may have implications for the potential mechanisms of AcS-mediated ITP relapse. Further studies are needed to confirm these results and to dissect spleen immunity in ITP.
Asunto(s)
Púrpura Trombocitopénica Idiopática , Enfermedades del Bazo , Trombocitopenia , Adulto , Humanos , Esplenectomía/métodos , RecurrenciaRESUMEN
Long non-coding RNA (lncRNA) are emerging as powerful and versatile regulators of transcriptional programs and distinctive biomarkers of progression of T-cell lymphoma. Their role in the aggressive anaplastic lymphoma kinase-negative (ALK-) subtype of anaplastic large cell lymphoma (ALCL) has been elucidated only in part. Starting from our previously identified ALCL-associated lncRNA signature and performing digital gene expression profiling of a retrospective cohort of ALCL, we defined an 11 lncRNA signature able to discriminate among ALCL subtypes. We selected a not previously characterized lncRNA, MTAAT, with preferential expression in ALK- ALCL, for molecular and functional studies. We demonstrated that lncRNA MTAAT contributes to an aberrant mitochondrial turnover restraining mitophagy and promoting cellular proliferation. Functionally, lncRNA MTAAT acts as a repressor of a set of genes related to mitochondrial quality control via chromatin reorganization. Collectively, our work demonstrates the transcriptional role of lncRNA MTAAT in orchestrating a complex transcriptional program sustaining the progression of ALK- ALCL.
Asunto(s)
Linfoma Anaplásico de Células Grandes , Linfoma de Células T Periférico , ARN Largo no Codificante , Humanos , Proteínas Tirosina Quinasas Receptoras/genética , Quinasa de Linfoma Anaplásico/genética , ARN Largo no Codificante/genética , Mitofagia/genética , Estudios Retrospectivos , Linfoma Anaplásico de Células Grandes/patologíaRESUMEN
Bone marrow (BM) studies are pivotal for the diagnosis of haematological disorders. Their introduction into clinical haematology dates back to the work of Giovanni Ghedini (1877-1959), an Italian physician who first conceived BM sampling in 1908. Ghedini's proposal stemmed from his clinical experience and from the scientific developments that characterised his epoch. By presenting selected passages of Ghedini's publications, this report considers the theoretical and historical bases of his work and analyses its practical implications for modern haematology.
Asunto(s)
Enfermedades Hematológicas , Hematología , Biopsia , Médula Ósea/patología , Examen de la Médula Ósea , Enfermedades Hematológicas/patología , HumanosRESUMEN
Thrombopoietin receptor agonists (TPO-RA) are a valid therapy for immune thrombocytopenia (ITP), due to megakaryocyte stimulation and (poorly characterised) immune-modulatory effects. The spleen is pivotal in the pathogenesis of ITP, yet little is known on its immune microenvironment and on effects of TPO-RA on this organ. To address these topics, we analysed 35 spleens removed for primary refractory ITP. Pre-splenectomy TPO-RA administration correlated with increased splenic regulatory T cells (Tregs), type 2 T-helper cells and histiocyte density and with reduced red pulp sinusoids. Surgical outcome was not associated with TPO-RA administration, other pre-splenectomy therapies and/or Treg density. In conclusion, TPO-RA affect the splenic microenvironment, but this has no impact on splenectomy outcome.
Asunto(s)
Púrpura Trombocitopénica Idiopática , Trombocitopenia , Humanos , Púrpura Trombocitopénica Idiopática/etiología , Receptores Fc , Receptores de Trombopoyetina/agonistas , Proteínas Recombinantes de Fusión , Bazo/patología , Linfocitos T Reguladores/patología , Trombocitopenia/complicaciones , Trombopoyetina/farmacología , Trombopoyetina/uso terapéuticoRESUMEN
Cancer cells undergo changes in metabolic and survival pathways that increase their malignancy. Isoform 2 of the glycolytic enzyme hexokinase (HK2) enhances both glucose metabolism and resistance to death stimuli in many neoplastic cell types. Here, we observe that HK2 locates at mitochondria-endoplasmic reticulum (ER) contact sites called MAMs (mitochondria-associated membranes). HK2 displacement from MAMs with a selective peptide triggers mitochondrial Ca2+ overload caused by Ca2+ release from ER via inositol-3-phosphate receptors (IP3Rs) and by Ca2+ entry through plasma membrane. This results in Ca2+ -dependent calpain activation, mitochondrial depolarization and cell death. The HK2-targeting peptide causes massive death of chronic lymphocytic leukemia B cells freshly isolated from patients, and an actionable form of the peptide reduces growth of breast and colon cancer cells allografted in mice without noxious effects on healthy tissues. These results identify a signaling pathway primed by HK2 displacement from MAMs that can be activated as anti-neoplastic strategy.
Asunto(s)
Hexoquinasa , Neoplasias , Animales , Muerte Celular , Retículo Endoplásmico/metabolismo , Hexoquinasa/genética , Hexoquinasa/metabolismo , Humanos , Ratones , Mitocondrias , Membranas Mitocondriales/metabolismo , Neoplasias/metabolismoRESUMEN
Osteopontin (OPN) is a phosphoglycoprotein secreted into the extracellular matrix upon liver injury, acting as a cytokine stimulates the deposition of fibrillary collagen in liver fibrogenesis. In livers of mice subjected to bile duct ligation (BDL) and in cultured activated hepatic stellate cells (HSCs), we show that OPN, besides being overexpressed, is substantially phosphorylated by family with sequence similarity 20, member C (Fam20C), formerly known as Golgi casein kinase (G-CK), which is exclusively resident in the Golgi apparatus. In both experimental models, Fam20C becomes overactive when associated with a 500-kDa multiprotein complex, as compared with the negligible activity in livers of sham-operated rats and in quiescent HSCs. Fam20C knockdown not only confirmed the role of Fam20C itself in OPN phosphorylation, but also revealed that phosphorylation was essential for OPN secretion. However, OPN acts as a fibrogenic factor independently of its phosphorylation state, as demonstrated by the increased expression of Collagen-I by HSCs incubated with either a phosphorylated or nonphosphorylated form of recombinant OPN. Collectively, our results confirm that OPN promotes liver fibrosis and highlight Fam20C as a novel factor driving this process by favoring OPN secretion from HSCs, opening new avenues for deciphering yet unidentified mechanisms underlying liver fibrogenesis.
Asunto(s)
Proteínas de Unión al Calcio/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Células Estrelladas Hepáticas/metabolismo , Hígado/patología , Osteopontina/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Animales , Citocinas/metabolismo , Hígado/metabolismo , Cirrosis Hepática/metabolismo , Masculino , Ratones , Ratones Noqueados , Fosforilación , Ratas , Ratas Wistar , Transducción de SeñalRESUMEN
OBJECTIVE: Immune thrombocytopenia (ITP) is an acquired disorder, characterized by immune-mediated platelet destruction. The spleen plays a key pathogenic role in ITP and splenectomy is a valuable second-line therapy for this disease. Little is known on ITP spleen histology and response to splenectomy is unpredictable. This study aims to characterize ITP spleen histology and assess possible predictors of splenectomy outcome. METHODS: A series of 23 ITP spleens were retrospectively assessed for the following histological parameters: density of lymphoid follicles (LFs), marginal zones (MZs), T helper and cytotoxic T cells; presence of reactive germinal centers (GCs); width of perivascular T cell sheaths; and red pulp features. Clinical and histological data were matched with postsplenectomy platelet counts to assess their prognostic relevance. RESULTS: Three histological patterns were documented: a hyperplastic white pulp pattern, a non-activated white pulp pattern (lacking GCs), and a white pulp-depleted pattern. Poor surgical responses were associated with presplenectomy high-dose steroid administration, autoimmune comorbidities and low T follicular helper cell density. The combination of such parameters stratified patients into different splenectomy response groups. The removal of accessory spleens was also associated with better outcome. CONCLUSION: ITP spleens are histologically heterogeneous and clinical-pathological parameters may help predict the splenectomy outcome.
Asunto(s)
Púrpura Trombocitopénica Idiopática/diagnóstico , Bazo/patología , Adolescente , Adulto , Anciano , Autoinmunidad , Biopsia , Terapia Combinada , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Pronóstico , Púrpura Trombocitopénica Idiopática/etiología , Púrpura Trombocitopénica Idiopática/mortalidad , Púrpura Trombocitopénica Idiopática/terapia , Estudios Retrospectivos , Esplenectomía , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Resultado del Tratamiento , Adulto JovenRESUMEN
AIMS: Classic Hodgkin lymphoma (cHL) is a common malignancy of the pediatric age. Although clinical-radiological features are routinely used for disease risk stratification, the role of tumor histology has yet to be defined. This study aimed to characterize the clinical-pathological features of a large cohort of pediatric cHL specifically investigating the relevance of tumor histology for the prognostic stratification of patients. METHODS AND RESULTS: The study considered 96 clinically annotated cases of pediatric cHL treated according to the AIEOP-LH2004 protocol. The following histological parameters were considered: (i) cHL variant; (ii) grade of nodular sclerosis (NS); (iii) staining for Bcl2 and p53, and expression of B-cell (BCA) and T-cell antigens (TCA) by Hodgkin/Reed-Sternberg cells. The study population consisted of 51 males and 45 females (median age: 13.6 years) with five-year overall and progression-free survival of 94% and 81%, respectively. Most cases featured NS morphology (96%) with a prevalence of NS1 over NS2 grades. Two NS2 variants were recognized (sarcomatous/syncytial and fibrohistiocytic). A consistent subset of cases disclosed positivity for BCA (34%), TCA (26%), p53 (13%), and Bcl2 (19%). Clinical-pathological correlations showed a more aggressive clinical course for NS2 over NS1 cases. The NS2 fibrohistiocytic variant was associated with the worst outcome. No other histological features correlated with prognosis. CONCLUSIONS: Pediatric cHL is a clinically and histologically heterogeneous neoplasm. The majority of cases disclose NS morphology and aberrant phenotypes are frequently encountered. In the pediatric population, NS grading and NS2 subtyping bear significant prognostic impact.
Asunto(s)
Enfermedad de Hodgkin , Proteínas de Neoplasias/metabolismo , Células de Reed-Sternberg , Adolescente , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Enfermedad de Hodgkin/metabolismo , Enfermedad de Hodgkin/mortalidad , Enfermedad de Hodgkin/patología , Humanos , Masculino , Células de Reed-Sternberg/metabolismo , Células de Reed-Sternberg/patología , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
Among fungal infection, mucormycosis is a rare but severe etiology in immunocompromised patients. Lung and sinus are the usual sites; the involvement of blood vessels is also described. The diagnosis is a real challenge, because blood tests (galactomannan, beta-D-glucan) are negative and the only diagnostic tool is usually the biopsy of the affected zone. Aortitis is rare and usually caused by bacterial infection, fungal etiology is unusual and only episodic cases are reported in literature. Medical therapy alone is usually not sufficient and debilitating surgical intervention is required. We report the case of a child affected by B precursor acute lymphoblastic leukemia, presenting a systemic fungal infection complicated by aortitis, probably due to Mucor. The patient developed fever and pneumonia during the Induction phase of chemotherapy. At the beginning, the infection was treated as bacterial and the diagnosis of Mucor infection was possible only after surgical intervention with histological analysis. Medical therapy (antifungal) was not sufficient alone to cure the infection and an urgent surgical intervention was required. This case underlines the challenge in the diagnosis of mucomycosis, that should be suspected in case of prolonged fever during aplasia, not responding to standard antibiotic and antifungal therapies. Mucor infection often require a combined intervention, both medical and surgical to cure the infection.
Asunto(s)
Aorta/patología , Mucormicosis/etiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Niño , Femenino , Humanos , Mucormicosis/patologíaRESUMEN
The gastrointestinal tract (GI) is the primary site of lymphoproliferative lesions, spanning from reactive lymphoid hyperplasia to overt lymphoma. The diagnosis of these diseases is challenging and an integrated approach based on clinical, morphological, immunohistochemical and molecular data is needed. To reach to confident conclusions, a stepwise approach is highly recommended. Histological evaluation should first assess the benign versus neoplastic nature of a given lymphoid infiltrate. Morphological and phenotypic analyses should then be applied to get to a definite diagnosis.This review addresses the key histological features and diagnostic workup of the most common GI non-Hodgkin lymphomas (NHLs). Differential diagnoses and possible pitfalls are discussed by considering distinct groups of lesions (i.e. small to medium B-cell NHLs; medium to large B-cell NHLs; T-cell NHLs; and mimickers of Hodgkin lymphoma). The key clinical and epidemiological features of each entity are also described.
Asunto(s)
Diagnóstico Diferencial , Neoplasias Gastrointestinales , Trastornos Linfoproliferativos , Neoplasias Gastrointestinales/diagnóstico , Neoplasias Gastrointestinales/patología , Tracto Gastrointestinal/patología , Enfermedad de Hodgkin/diagnóstico , Enfermedad de Hodgkin/patología , Humanos , Linfoma de Células B/diagnóstico , Linfoma de Células B/patología , Linfoma no Hodgkin/diagnóstico , Linfoma no Hodgkin/patología , Linfoma de Células T/diagnóstico , Linfoma de Células T/patología , Trastornos Linfoproliferativos/diagnóstico , Trastornos Linfoproliferativos/patologíaRESUMEN
We evaluated differences in density and 18F-FDG PET/MRI features of lytic bone lesions (LBLs) identified by whole-body low-dose CT (WB-LDCT) in patients affected by newly diagnosed multiple myeloma (MM). In 18 MM patients, 135 unequivocal LBLs identified by WB-LDCT were characterized for inner density (negative or positive Hounsfield unit (HU)), where negative density (HU < 0) characterizes normal yellow marrow whereas positive HU correlates with tissue-like infiltrative pattern. The same LBLs were analyzed by 18F-FDG PET/DWI-MRI, registering DWI signal with ADC and SUV max values. According to HU, 35 lesions had a negative density (- 56.94 ± 31.87 HU) while 100 lesions presented positive density (44.87 ± 23.89 HU). In seven patients, only positive HU LBLs were demonstrated whereas in eight patients, both positive and negative HU LBLs were detected. Intriguingly, in three patients (16%), only negative HU LBLs were shown. At 18F-FDG PET/DWI-MRI analysis, negative HU LBLs presented low ADC values (360.69 ± 154.38 × 10-6 mm2/s) and low SUV max values (1.69 ± 0.56), consistent with fatty marrow, whereas positive HU LBLs showed an infiltrative pattern, characterized by higher ADC (mean 868.46 ± 207.67 × 10-6 mm2/s) and SUV max (mean 5.04 ± 1.94) values. Surprisingly, histology of negative HU LBLs documented infiltration by neoplastic plasma cells scattered among adipocytes. In conclusion, two different patterns of LBLs were detected by WB-LDCT in MM patients. Both types of lesions were indicative for active disease, although only positive HU LBL were captured by 18F-FDG PET/DWI-MRI imaging, indicating that WB-LDCT adds specific information.
Asunto(s)
Imagen Multimodal/métodos , Mieloma Múltiple/diagnóstico por imagen , Osteólisis/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Tomografía Computarizada por Rayos X/métodos , Imagen de Cuerpo Entero/métodos , Adulto , Anciano , Médula Ósea/diagnóstico por imagen , Imagen de Difusión por Resonancia Magnética/métodos , Femenino , Radioisótopos de Flúor , Fluorodesoxiglucosa F18 , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/complicaciones , Osteólisis/etiología , Osteólisis/metabolismo , RadiofármacosRESUMEN
Mastocytosis is a rare disease in which heightened amounts of mast cells accumulate in the skin, bone marrow, and other visceral organs. Upon activation, mast cells release a wide variety of preformed or newly synthesized mediators which can induce allergic symptoms and inflammatory reactions. Mastocytosis is diagnosed by biopsy and can be divided into cutaneous and systemic mastocytosis (SM). The first one affects the skin and is relatively benign, whilst SM, which involves bone marrow and other organs, may be aggressive and associate with both myelodisplastic and myeloproliferative diseases. Here we present a case of SM associated with essential thrombocythemia and complicated by severe osteoporosis, successfully treated with hydroxyurea, low-dose aspirin and zolendronic acid.
Asunto(s)
Mastocitosis Sistémica/diagnóstico , Trombocitosis/etiología , Biopsia/métodos , Médula Ósea/patología , Humanos , Masculino , Mastocitosis Sistémica/diagnóstico por imagen , Mastocitosis Sistémica/fisiopatología , Persona de Mediana Edad , Trombocitosis/fisiopatologíaAsunto(s)
Leucemia Linfocítica Crónica de Células B , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Neoplasia Residual , Esplenomegalia , Rituximab/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Protocolos de Quimioterapia Combinada AntineoplásicaAsunto(s)
Linfadenopatía Inmunoblástica , Isocitrato Deshidrogenasa , Linfoma de Células T , Humanos , Linfadenopatía Inmunoblástica/diagnóstico , Linfadenopatía Inmunoblástica/genética , Isocitrato Deshidrogenasa/genética , Linfoma de Células T/diagnóstico , Linfoma de Células T/genética , Mutación , Estudios RetrospectivosRESUMEN
The central role of the microRNA (miR) 15a/16-1 cluster in B-cell oncogenesis has been extensively demonstrated, with over two-thirds of B-cell chronic lymphocytic leukemia characterized by the deletion of the miR-15a/16-1 locus at 13q14. Despite the well-established understanding of the molecular mechanisms occurring during miR-15a/16-1 dysregulation, the oncogenic role of other miR-15/16 family members, such as the miR-15b/16-2 cluster (3q25), is still far from being elucidated. Whereas miR-15a is highly similar to miR-15b, miR-16-1 is identical to miR-16-2; thus, it could be speculated that both clusters control a similar set of target genes and may have overlapping functions. However, the biological role of miR-15b/16-2 is still controversial. We generated miR-15b/16-2 knockout mice to better understand the cluster's role in vivo. These mice developed B-cell malignancy by age 15-18 mo with a penetrance of 60%. At this stage, mice showed significantly enlarged spleens with abnormal B cell-derived white pulp enlargement. Flow cytometric analysis demonstrated an expanded CD19+ CD5+ population in the spleen of 40% knockout mice, a characteristic of the chronic lymphocytic leukemia-associated phenotype found in humans. Of note, miR-15b/16-2 modulates the CCND2 (Cyclin D2), CCND1 (Cyclin D1), and IGF1R (insulin-like growth factor 1 receptor) genes involved in proliferation and antiapoptotic pathways in mouse B cells. These results are the first, to our knowledge, to suggest an important role of miR-15b/16-2 loss in the pathogenesis of B-cell chronic lymphocytic leukemia.
Asunto(s)
Eliminación de Gen , Regulación Leucémica de la Expresión Génica , Leucemia Linfocítica Crónica de Células B/genética , MicroARNs/genética , Animales , Ciclina D1/genética , Ciclina D2/genética , Perfilación de la Expresión Génica , Células HEK293 , Humanos , Leucemia Linfocítica Crónica de Células B/inmunología , Ratones , Ratones Noqueados , Receptor IGF Tipo 1/genéticaRESUMEN
PURPOSE OF REVIEW: Patient-derived tumor xenografts (PDTXs) have emerged as powerful platforms in medical oncology. A plethora of PDTXs were generated to study solid cancers, but limited data are as yet available on hematological diseases. The aim of this review is to describe the state of art of lymphoma PDTXs, discussing future directions for the development of integrated/personalized cancer programs. RECENT FINDINGS: In the last decades, several PDTXs of lymphoproliferative disorders have been produced. Most studies focused on acute lymphoblastic leukemias, but consistent results have recently been obtained also for indolent and aggressive B-/T-cell lymphomas. These models have contributed to characterize lymphoma biology and therapy, despite technical and scientific issues have partially limited their application (e.g. high costs, relatively low engraftment rates, lack of human-derived tumor microenvironment, clonal selection of engrafted cells, limited characterization of tumor grafts). In the next future, such limitations should be overcome by new technical approaches and dedicated multiinstitutional programs. SUMMARY: PDTXs represent an unprecedented opportunity to study the biology and clinical management of lymphoproliferative disorders. Many of the current models display limitations, which will be resolved by rigorous approaches and comprehensive libraries, recapitulating the extreme heterogeneity of such neoplasms.