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1.
Cancers (Basel) ; 16(12)2024 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-38927876

RESUMEN

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy and a heterogeneous entity comprised of several biologically distinct subtypes. Recently, novel genetic classifications of DLBCL have been resolved based on common mutational patterns indicative of distinct pathways of transformation. However, the complicated and costly nature of the novel classifiers has precluded their inclusion into routine practice. In view of this, the status of the TP53 gene, which is mutated or deleted in 20-30% of the cases, has emerged as an important prognostic factor for DLBCL patients, setting itself apart from other predictors. TP53 genetic lesions are particularly enriched in a genetic subtype of DLBCL that shares genomic features with Richter Syndrome, highlighting the possibility of a subset of DLBCL arising from the transformation of an occult chronic lymphocytic leukemia-like malignancy, such as monoclonal B-cell lymphocytosis. Patients with TP53-mutated DLBCL, including those with Richter Syndrome, have a particularly poor prognosis and display inferior responses to standard chemoimmunotherapy regimens. The data presented in this manuscript argue for the need for improved and more practical risk-stratification models for patients with DLBCL and show the potential for the use of TP53 mutational status for prognostication and, in prospect, treatment stratification in DLBCL.

2.
Blood ; 2024 Apr 29.
Artículo en Inglés | MEDLINE | ID: mdl-38684038

RESUMEN

The T-box transcription factor T-bet is known as a master regulator of T-cell response but its role in malignant B cells is not sufficiently explored. Here, we conducted single-cell resolved multi-omics analyses of malignant B cells from patients with chronic lymphocytic leukemia (CLL) and studied a CLL mouse model with genetic knockout of TBX21. We found that T-bet acts as a tumor suppressor in malignant B cells by decreasing their proliferation rate. NF-κB activity induced by inflammatory signals provided by the microenvironment, triggered T-bet expression which impacted on promoter proximal and distal chromatin co-accessibility and controlled a specific gene signature by mainly suppressing transcription. Gene set enrichment analysis identified a positive regulation of interferon signaling, and a negative control of proliferation by T-bet. In line, we showed that T-bet represses cell cycling and is associated with longer overall survival of CLL patients. Our study uncovers a novel tumor suppressive role of T-bet in malignant B cells via its regulation of inflammatory processes and cell cycling which has implications for stratification and therapy of CLL patients. Linking T-bet activity to inflammation explains the good prognostic role of genetic alterations in inflammatory signaling pathways in CLL.

3.
Leukemia ; 38(7): 1511-1521, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38486128

RESUMEN

Loss-of-function mutations in NFKBIE, which encodes for the NF-κB inhibitor IκBε, are frequent in chronic lymphocytic leukemia (CLL) and certain other B-cell malignancies and have been associated with accelerated disease progression and inferior responses to chemotherapy. Using in vitro and in vivo murine models and primary patient samples, we now show that NFKBIE-mutated CLL cells are selected by microenvironmental signals that activate the NF-κB pathway and induce alterations within the tumor microenvironment that can allow for immune escape, including expansion of CD8+ T-cells with an exhausted phenotype and increased PD-L1 expression on the malignant B-cells. Consistent with the latter observations, we find increased expression of exhaustion markers on T-cells from patients with NFKBIE-mutated CLL. In addition, we show that NFKBIE-mutated murine CLL cells display selective resistance to ibrutinib and report inferior outcomes to ibrutinib treatment in NFKBIE-mutated CLL patients. These findings suggest that NFKBIE mutations can contribute to CLL progression through multiple mechanisms, including a bidirectional crosstalk with the microenvironment and reduced sensitivity to BTK inhibitor treatment.


Asunto(s)
Adenina , Leucemia Linfocítica Crónica de Células B , Mutación , Piperidinas , Escape del Tumor , Microambiente Tumoral , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/patología , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/inmunología , Microambiente Tumoral/inmunología , Humanos , Animales , Ratones , Adenina/análogos & derivados , Adenina/farmacología , Piperidinas/farmacología , Piperidinas/uso terapéutico , Escape del Tumor/genética , FN-kappa B/metabolismo , Linfocitos T CD8-positivos/inmunología , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Pirazoles/farmacología , Pirazoles/uso terapéutico
4.
Blood Adv ; 8(8): 1920-1933, 2024 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-38359376

RESUMEN

ABSTRACT: This works defines, to the best of our knowledge, for the first time a molecular circuit connecting nicotinamide mononucleoside phosphoribosyl transferase (NAMPT) activity to the B-cell receptor (BCR) pathway. Using 4 distinct xenograft models derived from patients with Richter syndrome (RS-PDX), we show that BCR cross-linking results in transcriptional activation of the nicotinamide adenine dinucleotide (NAD) biosynthetic enzyme NAMPT, with increased protein expression, in turn, positively affecting global cellular NAD levels and sirtuins activity. NAMPT blockade, by using the novel OT-82 inhibitor in combination with either BTK or PI3K inhibitors (BTKi or PI3Ki), induces rapid and potent apoptotic responses in all 4 models, independently of their mutational profile and the expression of the other NAD biosynthetic enzymes, including nicotinate phosphoribosyltransferase. The connecting link in the circuit is represented by AKT that is both tyrosine- and serine-phosphorylated by PI3K and deacetylated by sirtuin 1 and 2 to obtain full kinase activation. Acetylation (ie, inhibition) of AKT after OT-82 administration was shown by 2-dimensional gel electrophoresis and immunoprecipitation. Consistently, pharmacological inhibition or silencing of sirtuin 1 and 2 impairs AKT activation and induces apoptosis of RS cells in combination with PI3Ki or BTKi. Lastly, treatment of RS-PDX mice with the combination of PI3Ki and OT-82 results in significant inhibition of tumor growth, with evidence of in vivo activation of apoptosis. Collectively, these data highlight a novel application for NAMPT inhibitors in combination with BTKi or PI3Ki in aggressive lymphomas.


Asunto(s)
Benzamidas , Leucemia Linfocítica Crónica de Células B , Linfoma de Células B Grandes Difuso , Pirazoles , Piridinas , Humanos , Animales , Ratones , NAD/metabolismo , Sirtuina 1/genética , Sirtuina 1/metabolismo , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Nicotinamida Fosforribosiltransferasa
5.
Sci Rep ; 13(1): 16950, 2023 10 07.
Artículo en Inglés | MEDLINE | ID: mdl-37805613

RESUMEN

Despite recent relevant therapeutic progresses, chronic lymphocytic leukemia (CLL) remains an incurable disease. Selinexor, an oral inhibitor of the nuclear export protein XPO1, is active as single agent in different hematologic malignancies, including CLL. The purpose of this study was to evaluate the anti-tumor effects of selinexor, used in combination with chemotherapy drugs (i.e. fludarabine and bendamustine) or with the PI3Kδ inhibitor idelalisib in CLL. Our results showed a significant decrease in CLL cell viability after treatment with selinexor-containing drug combinations compared to each single compound, with demonstration of synergistic cytotoxic effects. Interestingly, this drug synergism was exerted also in the presence of the protective effect of stromal cells. From the molecular standpoint, the synergistic cytotoxic activity of selinexor plus idelalisib was associated with increased regulatory effects of this drug combination on the tumor suppressors FOXO3A and IkBα compared to each single compound. Finally, selinexor was also effective in potentiating the in vivo anti-tumor effects of the PI3Kδ inhibitor in mice treated with the drug combination compared to single agents. Our data provide preclinical evidence of the synergism and potential efficacy of a combination treatment targeting XPO1 and PI3Kδ in CLL.


Asunto(s)
Antineoplásicos , Leucemia Linfocítica Crónica de Células B , Animales , Ratones , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/patología , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Hidrazinas/farmacología , Hidrazinas/uso terapéutico , Combinación de Medicamentos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico
6.
Front Oncol ; 13: 1216398, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37260980
7.
Blood ; 141(26): 3166-3183, 2023 06 29.
Artículo en Inglés | MEDLINE | ID: mdl-37084385

RESUMEN

Dysregulation of messenger RNA (mRNA) translation, including preferential translation of mRNA with complex 5' untranslated regions such as the MYC oncogene, is recognized as an important mechanism in cancer. Here, we show that both human and murine chronic lymphocytic leukemia (CLL) cells display a high translation rate, which is inhibited by the synthetic flavagline FL3, a prohibitin (PHB)-binding drug. A multiomics analysis performed in samples from patients with CLL and cell lines treated with FL3 revealed the decreased translation of the MYC oncogene and of proteins involved in cell cycle and metabolism. Furthermore, inhibiting translation induced a proliferation arrest and a rewiring of MYC-driven metabolism. Interestingly, contrary to other models, the RAS-RAF-(PHBs)-MAPK pathway is neither impaired by FL3 nor implicated in translation regulation in CLL cells. Here, we rather show that PHBs are directly associated with the eukaryotic initiation factor (eIF)4F translation complex and are targeted by FL3. Knockdown of PHBs resembled FL3 treatment. Importantly, inhibition of translation controlled CLL development in vivo, either alone or combined with immunotherapy. Finally, high expression of translation initiation-related genes and PHBs genes correlated with poor survival and unfavorable clinical parameters in patients with CLL. Overall, we demonstrated that translation inhibition is a valuable strategy to control CLL development by blocking the translation of several oncogenic pathways including MYC. We also unraveled a new and direct role of PHBs in translation initiation, thus creating new therapeutic opportunities for patients with CLL.


Asunto(s)
Leucemia Linfocítica Crónica de Células B , Humanos , Ratones , Animales , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/metabolismo , Factor 4F Eucariótico de Iniciación/genética , Prohibitinas , Genes myc , ARN Mensajero/genética
8.
Blood ; 140(22): 2335-2347, 2022 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-36084319

RESUMEN

A large amount of circumstantial evidence has accumulated suggesting that Toll-like receptor (TLR) signals are involved in driving chronic lymphocytic leukemia (CLL) cell proliferation, but direct in vivo evidence for this is still lacking. We have now further addressed this possibility by pharmacologically inhibiting or genetically inactivating the TLR pathway in murine CLL and human Richter syndrome (RS) patient-derived xenograft (PDX) cells. Surprisingly, we show that pharmacologic inhibition of TLR signaling by treatment with an IRAK1/4 inhibitor delays the growth of the transplanted malignant cells in recipient mice, but genetic inactivation of the same pathway by CRISPR/Cas9-mediated disruption of IRAK4 or its proximal adaptor MyD88 has no effect. We further show that treatment with the IRAK1/4 inhibitor results in depletion of macrophages and demonstrate that these cells can support the survival and enhance the proliferation of both murine Eµ-TCL1 leukemia and human RS cells. We also show that genetic disruption of the B-cell receptor (BCR) by CRISPR/Cas9 editing of the immunoglobulin M constant region gene inhibits the growth of human RS-PDX cells in vivo, consistent with our previous finding with murine Eµ-TCL1 leukemia cells. Finally, we show that genetic disruption of IRAK4 does not result in negative selection of human CLL cell lines xenografted in immunodeficient mice. The obtained data suggest that TLR signals are unlikely to represent a major driver of CLL/RS cell proliferation and provide further evidence that signals from macrophages and the BCR promote the growth and survival of CLL and RS cells in vivo.


Asunto(s)
Leucemia Linfocítica Crónica de Células B , Linfoma de Células B Grandes Difuso , Humanos , Ratones , Animales , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Quinasas Asociadas a Receptores de Interleucina-1/genética , Modelos Animales de Enfermedad , Receptores de Antígenos de Linfocitos B/metabolismo , Receptores Toll-Like , Macrófagos/metabolismo
9.
Front Immunol ; 13: 781364, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35296093

RESUMEN

Regulatory T cells (Tregs) are capable of inhibiting the proliferation, activation and function of T cells and play an important role in impeding the immune response to cancer. In chronic lymphocytic leukemia (CLL) a dysfunctional immune response and elevated percentage of effector-like phenotype Tregs have been described. In this study, using the Eµ-TCL1 mouse model of CLL, we evaluated the changes in the Tregs phenotype and their expansion at different stages of leukemia progression. Importantly, we show that Tregs depletion in DEREG mice triggered the expansion of new anti-leukemic cytotoxic T cell clones leading to leukemia eradication. In TCL1 leukemia-bearing mice we identified and characterized a specific Tregs subpopulation, the phenotype of which suggests its role in the formation of an immunosuppressive microenvironment, supportive for leukemia survival and proliferation. This observation was also confirmed by the gene expression profile analysis of these TCL1-specific Tregs. The obtained data on Tregs are consistent with those described so far, however, above all show that the changes in the Tregs phenotype described in CLL result from the formation of a specific, described in this study Tregs subpopulation. In addition, functional tests revealed the ability of Tregs to inhibit T cells that recognize model antigens expressed by leukemic cells. Moreover, inhibition of Tregs with a MALT1 inhibitor provided a therapeutic benefit, both as monotherapy and also when combined with an immune checkpoint inhibitor. Altogether, activation of Tregs appears to be crucial for CLL progression.


Asunto(s)
Leucemia Linfocítica Crónica de Células B , Animales , Modelos Animales de Enfermedad , Inmunidad , Inmunosupresores/uso terapéutico , Ratones , Linfocitos T Reguladores , Microambiente Tumoral
10.
Cancers (Basel) ; 13(16)2021 Aug 23.
Artículo en Inglés | MEDLINE | ID: mdl-34439393

RESUMEN

Membrane-bound CD200 is overexpressed in chronic lymphocytic leukemia (CLL), and there is some evidence that its soluble ectodomain (sCD200) could also be involved in the pathophysiology and the disease. However, very little is known about sCD200's prognostic significance. sCD200 was tested at diagnosis in 272 patients with CLL and in 78 age- and sex-matched healthy subjects using a specific human CD200 (OX-2 membrane glycoprotein) ELISA kit. A significantly higher concentration of sCD200 was found in CLL patients compared to controls. In our cohort, sCD200 was significantly higher in patients who were older than 66 years, with Binet stage C, unmutated IgVH and unfavorable (del11q or del17p) FISH. Time-to-first treatment and overall survival were significantly shorter in patients with higher sCD200 concentration, using as a cut-off 1281 pg/mL, the median value for sCD200 concentration in the whole CLL cohort. However, the prognostic impact of sCD200 was not confirmed in multivariate analysis. Baseline sCD200 values appeared to have an impact on the response to chemotherapy or chemo-immunotherapy, but not to targeted agents. Collectively, our data show that sCD200 serum levels correlate with more aggressive clinical and biological features and are able to predict a worse prognosis. This work supports the relevant role of CD200 not only as a diagnostic tool but also as a prognostic indicator and a potential therapeutic target in CLL.

11.
Blood ; 138(12): 1053-1066, 2021 09 23.
Artículo en Inglés | MEDLINE | ID: mdl-33900379

RESUMEN

B-cell receptor (BCR) signals play a critical role in the pathogenesis of chronic lymphocytic leukemia (CLL), but their role in regulating CLL cell proliferation has still not been firmly established. Unlike normal B cells, CLL cells do not proliferate in vitro upon engagement of the BCR, suggesting that CLL cell proliferation is regulated by other signals from the microenvironment, such as those provided by Toll-like receptors or T cells. Here, we report that BCR engagement of human and murine CLL cells induces several positive regulators of the cell cycle, but simultaneously induces the negative regulators CDKN1A, CDKN2A, and CDKN2B, which block cell-cycle progression. We further show that introduction of genetic lesions that downregulate these cell-cycle inhibitors, such as inactivating lesions in CDKN2A, CDKN2B, and the CDKN1A regulator TP53, leads to more aggressive disease in a murine in vivo CLL model and spontaneous proliferation in vitro that is BCR dependent but independent of costimulatory signals. Importantly, inactivating lesions in CDKN2A, CDKN2B, and TP53 frequently co-occur in Richter syndrome (RS), and BCR stimulation of human RS cells with such lesions is sufficient to induce proliferation. We also show that tumor cells with combined TP53 and CDKN2A/2B abnormalities remain sensitive to BCR-inhibitor treatment and are synergistically sensitive to the combination of a BCR and cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor both in vitro and in vivo. These data provide evidence that BCR signals are directly involved in driving CLL cell proliferation and reveal a novel mechanism of Richter transformation.


Asunto(s)
Transformación Celular Neoplásica , Inhibidor p15 de las Quinasas Dependientes de la Ciclina , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Leucemia Linfocítica Crónica de Células B , Receptores de Antígenos de Linfocitos B , Transducción de Señal , Proteína p53 Supresora de Tumor , Animales , Línea Celular Tumoral , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/inmunología , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/inmunología , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/inmunología , Humanos , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/inmunología , Ratones , Receptores de Antígenos de Linfocitos B/genética , Receptores de Antígenos de Linfocitos B/inmunología , Transducción de Señal/genética , Transducción de Señal/inmunología , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/inmunología
12.
Front Oncol ; 10: 584427, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33324560

RESUMEN

CD200, a transmembrane type Ia glycoprotein belonging to the immunoglobulin protein superfamily, is broadly expressed on a wide variety of cell types, such as B lymphocytes, a subset of T lymphocytes, dendritic cells, endothelial and neuronal cells. It delivers immunosuppressive signals through its receptor CD200R, which is expressed on monocytes/myeloid cells and T lymphocytes. Moreover, interaction of CD200 with CD200R has also been reported to play a role in the regulation of tumor immunity. Overexpression of CD200 has been reported in chronic lymphocytic leukemia (CLL) and hairy cell leukemia but not in mantle cell lymphoma, thus helping to better discriminate between these different B cell malignancies with different prognosis. In this review, we focus on the role of CD200 expression in the differential diagnosis of mature B-cell neoplasms and on the prognostic significance of CD200 expression in CLL, where conflicting results have been published so far. Of interest, increasing evidences indicate that anti-CD200 treatment might be therapeutically beneficial for treating CD200-expressing malignancies, such as CLL.

13.
Cancers (Basel) ; 12(11)2020 Nov 04.
Artículo en Inglés | MEDLINE | ID: mdl-33158264

RESUMEN

Chronic lymphocytic leukemia (CLL) is a common B cell malignancy and is the most common type of adult leukemia in western countries [...].

14.
Cell Death Dis ; 11(9): 769, 2020 09 17.
Artículo en Inglés | MEDLINE | ID: mdl-32943617

RESUMEN

Several cancer cell types, including chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBCL) upregulate antiapoptotic Bcl-2 to cope with oncogenic stress. BH3 mimetics targeting Bcl-2's hydrophobic cleft have been developed, including venetoclax as a promising anticancer precision medicine for treating CLL patients. Recently, BDA-366 was identified as a small molecule BH4-domain antagonist that could kill lung cancer and multiple myeloma cells. BDA-366 was proposed to switch Bcl-2 from an antiapoptotic into a proapoptotic protein, thereby activating Bax and inducing apoptosis. Here, we scrutinized the therapeutic potential and mechanism of action of BDA-366 in CLL and DLBCL. Although BDA-366 displayed selective toxicity against both cell types, the BDA-366-induced cell death did not correlate with Bcl-2-protein levels and also occurred in the absence of Bcl-2. Moreover, although BDA-366 provoked Bax activation, it did neither directly activate Bax nor switch Bcl-2 into a Bax-activating protein in in vitro Bax/liposome assays. Instead, in primary CLL cells and DLBCL cell lines, BDA-366 inhibited the activity of the PI3K/AKT pathway, resulted in Bcl-2 dephosphorylation and reduced Mcl-1-protein levels without affecting the levels of Bcl-2 or Bcl-xL. Hence, our work challenges the current view that BDA-366 is a BH4-domain antagonist of Bcl-2 that turns Bcl-2 into a pro-apoptotic protein. Rather, our results indicate that other mechanisms beyond switching Bcl-2 conformation underlie BDA-366's cell-death properties that may implicate Mcl-1 downregulation and/or Bcl-2 dephosphorylation.


Asunto(s)
Antraquinonas/farmacología , Apoptosis , Etanolaminas/farmacología , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Calcio/metabolismo , Línea Celular Tumoral , Citosol/metabolismo , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Liposomas/metabolismo , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Neoplasias/metabolismo , Fosforilación , Conformación Proteica , Dominios Proteicos , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Transducción de Señal , Proteína X Asociada a bcl-2/metabolismo , Proteína bcl-X/metabolismo
15.
Br J Haematol ; 190(6): 901-908, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32712965

RESUMEN

The relationship between chronic lymphocytic leukaemia (CLL) and qualitative/quantitative gammaglobulin abnormalities is well established. Nevertheless, in order to better understand this kind of connection, we examined 1505 patients with CLL and divided them into four subgroups on the basis of immunoglobulin (Ig) aberrations at diagnosis. A total of 73 (4·8%), 149 (10%), 200 (13·2%) and 1083 (72%) patients were identified with IgM monoclonal gammopathy (IgM/CLL), IgG monoclonal gammopathy (IgG/CLL), hypogammaglobulinaemia (hypo-γ) and normal Ig levels (γ-normal) respectively. IgM paraprotein was significantly associated with a more advanced Binet/Rai stage and del(17p)/TP53 mutation, while IgG abnormalities correlated with a higher occurrence of trisomy 12. Patients with any type of Ig abnormality had shorter treatment-free survival (TFS) but no significant impact affecting overall survival (OS) compared to those with normal Ig levels.


Asunto(s)
Inmunoglobulina G , Inmunoglobulina M , Leucemia Linfocítica Crónica de Células B , Proteínas de Neoplasias , Paraproteinemias , Adulto , Anciano , Anciano de 80 o más Años , Deleción Cromosómica , Cromosomas Humanos Par 12 , Cromosomas Humanos Par 17/genética , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/genética , Inmunoglobulina M/sangre , Inmunoglobulina M/genética , Leucemia Linfocítica Crónica de Células B/sangre , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/mortalidad , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/sangre , Proteínas de Neoplasias/genética , Paraproteinemias/sangre , Paraproteinemias/genética , Paraproteinemias/mortalidad , Estudios Retrospectivos , Síndrome de Smith-Magenis/sangre , Síndrome de Smith-Magenis/genética , Síndrome de Smith-Magenis/mortalidad , Tasa de Supervivencia , Trisomía , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo
16.
Cancers (Basel) ; 12(6)2020 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-32481736

RESUMEN

The B cell receptor (BCR) pathway has been identified as a potential therapeutic target in a number of common B cell malignancies, including chronic lymphocytic leukemia, diffuse large B cell lymphoma, Burkitt lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone B cell lymphoma, and Waldenstrom's macroglobulinemia. This finding has resulted in the development of numerous drugs that target this pathway, including various inhibitors of the kinases BTK, PI3K, and SYK. Several of these drugs have been approved in recent years for clinical use, resulting in a profound change in the way these diseases are currently being treated. However, the response rates and durability of responses vary largely across the different disease entities, suggesting a different proportion of patients with an activated BCR pathway and different mechanisms of BCR pathway activation. Indeed, several antigen-dependent and antigen-independent mechanisms have recently been described and shown to result in the activation of distinct downstream signaling pathways. The purpose of this review is to provide an overview of the mechanisms responsible for the activation of the BCR pathway in different B cell malignancies and to correlate these mechanisms with clinical responses to treatment with BCR inhibitors.

19.
Sci Rep ; 9(1): 10116, 2019 07 12.
Artículo en Inglés | MEDLINE | ID: mdl-31300739

RESUMEN

ß thalassaemia intermedia (ßTI) are a heterogeneous group of disorders known to be extremely phenotypically diverse. This group is more complex to manage as no definitive treatment guidelines exist unlike for ß thalassaemia major (ßTM). There are only a few studies looking at genotype phenotype associations of ßTI outside the Mediterranean region. The reasons for the diverse clinical phenotype in ßTI are unknown. We categorized fifty Sri Lankan patients diagnosed with ßTI as mild, moderate or severe according to published criteria. DNA samples were genotyped for ß thalassaemia mutations, α globin genotype and copy number and known genetic modifiers of haemoglobin F production. There were 26/50 (52.0%) in mild group and 12/50 (24.0%) each in moderate and sever categories. 18/26 (69.2%) classified as mild were ß heterozygotes and 17/18 (94.4%) had excess α globin genes. 11/12 (91.6%) classified as moderate were ß heterozygotes and 8/11 (72.2%) had excess α globin genes. In contrast, 8/12 (66.7%) classified as severe were ß homozygotes and 7/8(87.5%) had α globin gene deletions. In Sri Lanka, co-inheritance of either excess α globin genes in ß thalassaemia heterozygotes or α globin gene deletions in ß thalassaemia homozygotes is a significant factor in modulating disease severity.


Asunto(s)
Globinas alfa/genética , Talasemia beta/etiología , Adolescente , Adulto , Anciano , Transfusión Sanguínea , Niño , Preescolar , Femenino , Estudios de Asociación Genética , Genotipo , Heterocigoto , Homocigoto , Humanos , Masculino , Persona de Mediana Edad , Mutación , Sri Lanka , Adulto Joven , Talasemia beta/genética , Talasemia beta/terapia
20.
Cancers (Basel) ; 11(7)2019 Jun 26.
Artículo en Inglés | MEDLINE | ID: mdl-31248056

RESUMEN

Chronic Lymphocytic Leukemia (CLL) patients with +12 have been reported to have specific clinical and biologic features. We performed an analysis of the association between demographic; clinical; laboratory; biologic features and outcome in CLL patients with +12 to identify parameters predictive of disease progression; time to treatment; and survival. The study included 487 treatment-naive CLL patients with +12 from 15 academic centers; diagnosed between January 2000 and July 2016; and 816 treatment-naïve patients with absence of Fluorescence In Situ Hybridization (FISH) abnormalities. A cohort of 250 patients with +12 CLL followed at a single US institution was used for external validation. In patients with +12; parameters associated with worse prognosis in the multivariate model were high Lactate DeHydrogenase (LDH) and ß-2-microglobulin and unmutated immunoglobulin heavy-chain variable region gene (IGHV). CLL patients with +12 and high LDH levels showed a shorter Progression-Free-Survival (PFS) (30 months vs. 65 months; p < 0.001), Treatment-Free-Survival (TFS) (33 months vs. 69 months; p < 0.001), Overall Survival (OS) (131 months vs. 181 months; p < 0.001) and greater CLL-related mortality (29% vs. 11% at 10 years; p < 0.001) when compared with +12 CLL patients with normal LDH levels. The same differences were observed in the validation cohort. These data suggest that serum LDH levels can predict PFS; TFS; OS and CLL-specific survival in CLL patients with +12.

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