Disruption of the physiologic balance between cell proliferation and death is a universal feature of all cancers. In general terms, human B-cell lymphomas can be subdivided into 2 main groups, low- ...and high-growth fraction lymphomas, according to the mechanisms through which this imbalance is achieved. Most types of low-growth fraction lymphomas are initiated by molecular events resulting in the inhibition of apoptosis, such as translocations affecting BCL2, in follicular lymphoma, or BCL10 and API2/MLT1, in mucosa-associated lymphoid tissue (MALT) lymphomas. This results in cell accumulation as a consequence of prolonged cell survival. In contrast, high-growth fraction lymphomas are characterized by an enhanced proliferative activity, as a result of the deregulation of oncogenes with cell cycle regulatory functions, such asBCL6, in large B-cell lymphoma, or c-myc, in Burkitt lymphoma. Low- and high-growth fraction lymphomas are both able to accumulate other alterations in cell cycle regulation, most frequently involving tumor suppressor genes such asp16INK4a, p53, andp27KIP1. As a consequence, these tumors behave as highly aggressive lymphomas. The simultaneous inactivation of several of these regulators confers increased aggressivity and proliferative advantage to tumoral cells. In this review we discuss our current knowledge of the alterations in each of these pathways, with special emphasis on the deregulation of cell cycle progression, in an attempt to integrate the available information within a global model that describes the contribution of these molecular changes to the genesis and progression of B-cell lymphomas.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of primary cutaneous T-cell lymphoproliferative processes, mainly composed of mycosis fungoides and Sézary syndrome, the aggressive forms of ...which lack an effective treatment. The molecular pathogenesis of CTCL is largely unknown, although neoplastic cells show increased signaling from T-cell receptors (TCRs). DNAs from 11 patients with CTCL, both normal and tumoral, were target-enriched and sequenced by massive parallel sequencing for a selection of 524 TCR–signaling-related genes. Identified variants were validated by capillary sequencing. Multiple mutations were found that affected several signaling pathways, such as TCRs, nuclear factor κB, or Janus kinase/signal transducer and activator of transcription, but PLCG1 was found to be mutated in 3 samples, 2 of which featured a redundant mutation (c.1034T>C, S345F) in exon 11 that affects the PLCx protein catalytic domain. This mutation was further analyzed by quantitative polymerase chain reaction genotyping in a new cohort of 42 patients with CTCL, where it was found in 19% of samples. Immunohistochemical analysis for nuclear factor of activated T cells (NFAT) showed that PLCG1-mutated cases exhibited strong NFAT nuclear immunostaining. Functional studies demonstrated that PLCG1 mutants elicited increased downstream signaling toward NFAT activation, and inhibition of this pathway resulted in reduced CTCL cell proliferation and cell viability. Thus, increased proliferative and survival mechanisms in CTCL may partially depend on the acquisition of somatic mutations in PLCG1 and other genes that are essential for normal T-cell differentiation.
•Activating mutations in PLCG1 are a frequent finding in tumoral CTCL samples. This raises the possibility of targeted therapies against PLCG1 signaling pathway, using calcineurin inhibitors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In human cancers, all cancerous cells carry the oncogenic genetic lesions. However, to elucidate whether cancer is a stem cell‐driven tissue, we have developed a strategy to limit oncogene expression ...to the stem cell compartment in a transgenic mouse setting. Here, we focus on the effects of the BCR‐ABLp210 oncogene, associated with chronic myeloid leukaemia (CML) in humans. We show that CML phenotype and biology can be established in mice by restricting BCR‐ABLp210 expression to stem cell antigen 1 (Sca1)+ cells. The course of the disease in Sca1‐BCR‐ABLp210 mice was not modified on STI571 treatment. However, BCR‐ABLp210‐induced CML is reversible through the unique elimination of the cancer stem cells (CSCs). Overall, our data show that oncogene expression in Sca1+ cells is all that is required to fully reprogramme it, giving rise to a full‐blown, oncogene‐specified tumour with all its mature cellular diversity, and that elimination of the CSCs is enough to eradicate the whole tumour.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Follicular lymphoma (FL) is the most frequent indolent non-Hodgkin lymphoma. Around 20% of patients suffer early disease progression within 24 months (POD24) of diagnosis. This study examined the ...significance of circulating tumor DNA (ctDNA) in predicting response to therapy and POD24 in patients with FL.
We collected 100 plasma samples, before and during the treatment, from 36 patients with FL prospectively enrolled in 8 Spanish hospitals. They were treated with a chemotherapy-rituximab regimen and followed up for a median of 3.43 years. We performed targeted deep sequencing in cell-free DNA (cfDNA) and tumor genomic DNA from 31 diagnostic biopsy samples.
Of the alterations detected in the diagnostic tissue samples, 73% (300/411) were also identified in basal cfDNA. The mean numbers of alterations per basal cfDNA sample in patients who suffered progression of disease within 24 months (POD24-pos) or did not achieve complete response (non-CR) were significantly higher than in POD24-neg or CR patients (unpaired samples t test, P = 0.0001 and 0.001, respectively). Pretreatment ctDNA levels, as haploid genome equivalents per milliliter of plasma, were higher in patients without CR (P = 0.02) and in POD24-pos patients compared with POD24-neg patients (P < 0.001). Dynamic analysis showed that ctDNA levels decreased dramatically after treatment, although the reduction was more significant in patients with CR and POD24-neg patients.
Basal ctDNA levels are associated with the risk of early progression and response to treatment in FL. cfDNA monitoring and genotyping during treatment and follow-up predict response to treatment and early progression.
Lymphoma research is a paradigm of the integration of basic and clinical research within the fields of diagnosis and therapy. Clinical, phenotypic, and genetic data are currently used to predict ...which patients could benefit from standard treatment. However, alternative therapies for patients at higher risk from refractoriness or relapse are usually empirically proposed, based on trial and error, without considering the genetic complexity of aggressive B-cell lymphomas. This is primarily due to the intricate mosaic of genetic and epigenetic alterations in lymphomas, which are an obstacle to the prediction of which drug will work for any given patient. Matching a patient’s genes to drug sensitivity by directly testing live tissues comprises the “precision medicine” concept. However, in the case of lymphomas, this concept should be expanded beyond genomics, eventually providing better treatment options for patients in need of alternative therapeutic approaches. We provide an overview of the most recent findings in diffuse large B-cell lymphomas genomics, from the classic functional models used to study tumor biology and the response to experimental treatments using cell lines and mouse models, to the most recent approaches with spheroid/organoid models. We also discuss their potential relevance and applicability to daily clinical practice.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Peripheral T-cell lymphomas (PTCL) are a heterogeneous entity of neoplasms with poor prognosis, a lack of effective therapies, and a largely unknown molecular pathology. Deregulated NF-κB activity ...has been associated with several lymphoproliferative diseases, but its importance in T-cell lymphomagenesis is poorly understood. We investigated the function of the NF-κB-inducing kinase (NIK), in this pathway and its role as a potential molecular target in T-cell lymphomas.
We used immunohistochemistry to analyze the expression of different NF-κB members in primary human PTCL samples and to study its clinical impact. With the aim of inhibiting the pathway, we used genetic silencing of NIK in several T-cell lymphoma cell lines and observed its effect on downstream targets and cell viability.
We showed that the NF-κB pathway was activated in a subset of PTCLs associated with poor overall survival. NIK was overexpressed in a number of PTCL cell lines and primary samples, and a pivotal role for NIK in the survival of these tumor cells was unveiled. NIK depletion led to a dramatic induction of apoptosis in NIK-overexpressing cell lines and also showed a more pronounced effect on cell survival than inhibitor of kappa B kinase (IKK) knockdown. NIK silencing induced a blockage of both classical and alternative NF-κB activation and reduced expression of several prosurvival and antiapoptotic factors.
The results of the present study indicate that NIK could be a promising therapeutic target in these aggressive malignancies.
B-cell lymphomas comprise an increasing number of clinicopathological entities whose characterization has historically been based mainly on histopathological features. In recent decades, the analysis ...of chromosomal aberrations as well as gene and miRNA expression profile studies have helped distinguish particular tumor types and also enabled the detection of a number of targets with therapeutic implications, such as those activated downstream of the B-cell receptor. Our ability to identify the mechanisms involved in B-cell lymphoma pathogenesis has been boosted recently through the use of Next Generation Sequencing techniques in the analysis of human cancer. This work summarizes the recent findings in the molecular pathogenesis of B-cell neoplasms with special focus on those clinically relevant somatic mutations with the potential to be explored as candidates for the development of new targeted therapies. Our work includes a comparison between the mutational indexes and ranges observed in B-cell lymphomas and also with other solid tumors and describes the most striking mutational data for the major B-cell neoplasms. This review describes a highly dynamic field that currently offers many opportunities for personalized therapy, although there is still much to be gained from the further molecular characterization of these clinicopathological entities.
Follicular lymphoma (FL) is the second most common non‐Hodgkin lymphoma (NHL) subtype. The histological transformation (HT) of FL is an event considered frequent in the natural history of this tumor. ...We studied the transformation rates, predictive factors, and treatment characteristics that may impact in the survival of patients with FL and HT. A total of 1074 patients diagnosed with FL were prospectively enrolled from 1990 to 2016 in a Spanish registry. Sixty‐four HTs were recorded based on clinical criteria (55%) or histological confirmation (45%). The cumulative incidence rate of transformation at 5 years is 7.3%. The 5‐year overall survival (OS) without HT was 85% (95% confidence interval CI, 70%‐90%) vs 66% (95% CI, 51%‐76%; P = 0.0012) with HT. Factors associated with HT were elevated lactate dehydrogenase (LDH) (odds ratio OR 1.83), intermediate‐high Follicular lymphoma international prognostic index (FLIPI) (OR 2.16‐OR 3.21), B symptoms (OR 2.46), or Eastern Cooperative Oncology Group (ECOG) 1 (OR 2.35). Treatment options related to HT were “watch and wait” or no rituximab or anthracyclines initially. A 5‐year OS for patients treated with chemotherapy before HT was 55% (95% CI, 38%‐69%) versus 81% (95% CI, 53%‐93%; P = 0.009) for those who had not received it. The HT rate has decreased after the introduction of rituximab, as has been previously described. The timing of this treatment had an impact on the survival of these patients.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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