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1.
Proc Natl Acad Sci U S A ; 121(31): e2409232121, 2024 Jul 30.
Artículo en Inglés | MEDLINE | ID: mdl-39047044

RESUMEN

Despite the availability of life-extending treatments for B cell leukemias and lymphomas, many of these cancers remain incurable. Thus, the development of new molecular targets and therapeutics is needed to expand treatment options. To identify new molecular targets, we used a forward genetic screen in mice to identify genes required for development or survival of lymphocytes. Here, we describe Zfp574, an essential gene encoding a zinc finger protein necessary for normal and malignant lymphocyte survival. We show that ZFP574 interacts with zinc finger protein THAP12 and promotes the G1-to-S-phase transition during cell cycle progression. Mutation of ZFP574 impairs nuclear localization of the ZFP574-THAP12 complex. ZFP574 or THAP12 deficiency results in cell cycle arrest and impaired lymphoproliferation. Germline mutation, acute gene deletion, or targeted degradation of ZFP574 suppressed Myc-driven B cell leukemia in mice, but normal B cells were largely spared, permitting long-term survival, whereas complete lethality was observed in control animals. Our findings support the identification of drugs targeting ZFP574-THAP12 as a unique strategy to treat B cell malignancies.


Asunto(s)
Linfocitos B , Animales , Ratones , Linfocitos B/metabolismo , Leucemia de Células B/genética , Leucemia de Células B/patología , Leucemia de Células B/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Ratones Endogámicos C57BL , Linfoma de Células B/genética , Linfoma de Células B/patología , Linfoma de Células B/metabolismo
3.
BMC Res Notes ; 16(1): 265, 2023 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-37817248

RESUMEN

OBJECTIVES: The aim of this data paper is to describe a collection of 33 genomic, transcriptomic and epigenomic sequencing datasets of the B-cell acute lymphoblastic leukemia (ALL) cell line REH. REH is one of the most frequently used cell lines for functional studies of pediatric ALL, and these data provide a multi-faceted characterization of its molecular features. The datasets described herein, generated with short- and long-read sequencing technologies, can both provide insights into the complex aberrant karyotype of REH, and be used as reference datasets for sequencing data quality assessment or for methods development. DATA DESCRIPTION: This paper describes 33 datasets corresponding to 867 gigabases of raw sequencing data generated from the REH cell line. These datasets include five different approaches for whole genome sequencing (WGS) on four sequencing platforms, two RNA sequencing (RNA-seq) techniques on two different sequencing platforms, DNA methylation sequencing, and single-cell ATAC-sequencing.


Asunto(s)
Leucemia de Células B , Leucemia Linfocítica Crónica de Células B , Niño , Humanos , Línea Celular , Epigenómica/métodos , Genómica , Leucemia de Células B/genética , Leucemia Linfocítica Crónica de Células B/genética , Transcriptoma , Línea Celular Tumoral
4.
Oncoimmunology ; 12(1): 2184143, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36875548

RESUMEN

Despite massive improvements in the treatment of B-ALL through CART-19 immunotherapy, a large number of patients suffer a relapse due to loss of the targeted epitope. Mutations in the CD19 locus and aberrant splicing events are known to account for the absence of surface antigen. However, early molecular determinants suggesting therapy resistance as well as the time point when first signs of epitope loss appear to be detectable are not enlightened so far. By deep sequencing of the CD19 locus, we identified a blast-specific 2-nucleotide deletion in intron 2 that exists in 35% of B-ALL samples at initial diagnosis. This deletion overlaps with the binding site of RNA binding proteins (RBPs) including PTBP1 and might thereby affect CD19 splicing. Moreover, we could identify a number of other RBPs that are predicted to bind to the CD19 locus being deregulated in leukemic blasts, including NONO. Their expression is highly heterogeneous across B-ALL molecular subtypes as shown by analyzing 706 B-ALL samples accessed via the St. Jude Cloud. Mechanistically, we show that downregulation of PTBP1, but not of NONO, in 697 cells reduces CD19 total protein by increasing intron 2 retention. Isoform analysis in patient samples revealed that blasts, at diagnosis, express increased amounts of CD19 intron 2 retention compared to normal B cells. Our data suggest that loss of RBP functionality by mutations altering their binding motifs or by deregulated expression might harbor the potential for the disease-associated accumulation of therapy-resistant CD19 isoforms.


Asunto(s)
Antígenos CD19 , Ribonucleoproteínas Nucleares Heterogéneas , Leucemia de Células B , Proteína de Unión al Tracto de Polipirimidina , Proteínas de Unión al ARN , Humanos , Sitios de Unión , Epítopos , Ribonucleoproteínas Nucleares Heterogéneas/genética , Mutación , Proteína de Unión al Tracto de Polipirimidina/genética , Proteínas de Unión al ARN/genética , Leucemia de Células B/genética
6.
Blood ; 140(17): 1858-1874, 2022 10 27.
Artículo en Inglés | MEDLINE | ID: mdl-35789258

RESUMEN

The discovery of humans with monogenic disorders has a rich history of generating new insights into biology. Here we report the first human identified with complete deficiency of nuclear factor of activated T cells 1 (NFAT1). NFAT1, encoded by NFATC2, mediates calcium-calcineurin signals that drive cell activation, proliferation, and survival. The patient is homozygous for a damaging germline NFATC2 variant (c.2023_2026delTACC; p.Tyr675Thrfs∗18) and presented with joint contractures, osteochondromas, and recurrent B-cell lymphoma. Absence of NFAT1 protein in chondrocytes caused enrichment in prosurvival and inflammatory genes. Systematic single-cell-omic analyses in PBMCs revealed an environment that promotes lymphomagenesis with accumulation of naïve B cells (enriched for oncogenic signatures MYC and JAK1), exhausted CD4+ T cells, impaired T follicular helper cells, and aberrant CD8+ T cells. This work highlights the pleiotropic role of human NFAT1, will empower the diagnosis of additional patients with NFAT1 deficiency, and further defines the detrimental effects associated with long-term use of calcineurin inhibitors.


Asunto(s)
Contractura , Leucemia de Células B , Osteocondroma , Humanos , Calcineurina/genética , Leucemia de Células B/genética , Leucemia de Células B/metabolismo , Recurrencia Local de Neoplasia , Factores de Transcripción NFATC/genética , Factores de Transcripción NFATC/metabolismo , Linfoma de Células B/genética , Linfoma de Células B/metabolismo
7.
Cells ; 11(7)2022 03 28.
Artículo en Inglés | MEDLINE | ID: mdl-35406703

RESUMEN

Despite the high rates of complete remission following chimeric antigen receptor (CAR) T cell therapy, its full capacity is currently limited by the generation of dysfunctional CAR T cells. Senescent or exhausted CAR T cells possess poor targeting and effector functions, as well as impaired cell proliferation and persistence in vivo. Strategies to detect, prevent or reverse T cell exhaustion are therefore required in order to enhance the effectiveness of CAR T immunotherapy. Here we report that CD19 CAR T cells from non-responding patients with B cell malignancies show enrichment of CD8+ cells with exhausted/senescent phenotype and display a distinct transcriptional signature with dysregulation of genes associated with terminal exhaustion. Furthermore, CAR T cells from non-responding patients exhibit reduced proliferative capacity and decreased IL-2 production in vitro, indicating functional impairment. Overall, our work reveals potential mediators of resistance, paving the way to studies that will enhance the efficacy and durability of CAR T therapy in B cell malignancies.


Asunto(s)
Inmunoterapia Adoptiva , Leucemia de Células B , Receptores Quiméricos de Antígenos , Antígenos CD19 , Linfocitos B , Humanos , Leucemia de Células B/genética , Leucemia de Células B/terapia
8.
Int J Mol Sci ; 23(7)2022 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-35409391

RESUMEN

We report incidence and deep molecular characteristics of lineage switch in 182 pediatric patients affected by B-cell precursor acute lymphoblastic leukemia (BCP-ALL), who were treated with blinatumomab. We documented six cases of lineage switch that occurred after or during blinatumomab exposure. Therefore, lineage conversion was found in 17.4% of all resistance cases (4/27) and 3.2% of relapses (2/63). Half of patients switched completely from BCP-ALL to CD19-negative acute myeloid leukemia, others retained CD19-positive B-blasts and acquired an additional CD19-negative blast population: myeloid or unclassifiable. Five patients had KMT2A gene rearrangements; one had TCF3::ZNF384 translocation. The presented cases showed consistency of gene rearrangements and fusion transcripts across initially diagnosed leukemia and lineage switch. In two of six patients, the clonal architecture assessed by IG/TR gene rearrangements was stable, while in others, loss of clones or gain of new clones was noted. KMT2A-r patients demonstrated very few additional mutations, while in the TCF3::ZNF384 case, lineage switch was accompanied by a large set of additional mutations. The immunophenotype of an existing leukemia sometimes changes via different mechanisms and with different additional molecular changes. Careful investigation of all BM compartments together with all molecular -minimal residual disease studies can lead to reliable identification of lineage switch.


Asunto(s)
Anticuerpos Biespecíficos , Leucemia de Células B , Leucemia Linfocítica Crónica de Células B , Leucemia Mieloide Aguda , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Anticuerpos Biespecíficos/genética , Anticuerpos Biespecíficos/uso terapéutico , Niño , Humanos , Leucemia de Células B/genética , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Mieloide Aguda/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Factores de Transcripción/genética , Translocación Genética
9.
EMBO J ; 41(7): e108397, 2022 04 04.
Artículo en Inglés | MEDLINE | ID: mdl-35156727

RESUMEN

While PAX5 is an important tumor suppressor gene in B-cell acute lymphoblastic leukemia (B-ALL), it is also involved in oncogenic translocations coding for diverse PAX5 fusion proteins. PAX5-JAK2 encodes a protein consisting of the PAX5 DNA-binding region fused to the constitutively active JAK2 kinase domain. Here, we studied the oncogenic function of the PAX5-JAK2 fusion protein in a mouse model expressing it from the endogenous Pax5 locus, resulting in inactivation of one of the two Pax5 alleles. Pax5Jak2/+ mice rapidly developed an aggressive B-ALL in the absence of another cooperating exogenous gene mutation. The DNA-binding function and kinase activity of Pax5-Jak2 as well as IL-7 signaling contributed to leukemia development. Interestingly, all Pax5Jak2/+ tumors lost the remaining wild-type Pax5 allele, allowing efficient DNA-binding of Pax5-Jak2. While we could not find evidence for a nuclear role of Pax5-Jak2 as an epigenetic regulator, high levels of active phosphorylated STAT5 and increased expression of STAT5 target genes were seen in Pax5Jak2/+ B-ALL tumors, implying that nuclear Pax5-Jak2 phosphorylates STAT5. Together, these data reveal Pax5-Jak2 as an important nuclear driver of leukemogenesis by maintaining phosphorylated STAT5 levels in the nucleus.


Asunto(s)
Janus Quinasa 2 , Leucemia de Células B , Factor de Transcripción PAX5 , Factor de Transcripción STAT5 , Animales , Janus Quinasa 2/genética , Leucemia de Células B/genética , Ratones , Mutación , Factor de Transcripción PAX5/genética , Factor de Transcripción STAT5/genética , Translocación Genética
10.
BMC Cancer ; 21(1): 1331, 2021 Dec 14.
Artículo en Inglés | MEDLINE | ID: mdl-34906116

RESUMEN

BACKGROUND: The clinical outcome of Philadelphia chromosome-negative B cell acute lymphoblastic leukemia (Ph-neg B-ALL) varies considerably from one person to another after clinical treatment due to lack of targeted therapies and leukemia's heterogeneity. Ferroptosis is a recently discovered programmed cell death strongly correlated with cancers. Nevertheless, few related studies have reported its significance in acute lymphoblastic leukemia. METHODS: Herein, we collected clinical data of 80 Ph-neg B-ALL patients diagnosed in our center and performed RNA-seq with their initial bone marrow fluid samples. Throughout unsupervised machine learning K-means clustering with 24 ferroptosis related genes (FRGs), the clustered patients were parted into three variant risk groups and were performed with bioinformatics analysis. RESULTS: As a result, we discovered significant heterogeneity of both immune microenvironment and genomic variance. Furthermore, the immune check point inhibitors response and potential implementation of Sorafenib in Ph-neg B-ALL was also analyzed in our cohort. Lastly, one prognostic model based on 8 FRGs was developed to evaluate the risk of Ph-neg B-ALL patients. CONCLUSION: Jointly, our study proved the crucial role of ferroptosis in Ph-neg B-ALL and Sorafenib is likely to improve the survival of high-risk Ph-neg B-ALL patients.


Asunto(s)
Ferroptosis/genética , Leucemia de Células B/genética , Leucemia de Células B/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Adolescente , Adulto , Antineoplásicos/uso terapéutico , Apoptosis , Niño , Análisis por Conglomerados , Femenino , Ferroptosis/inmunología , Humanos , Leucemia de Células B/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Pronóstico , RNA-Seq , Factores de Riesgo , Sorafenib/uso terapéutico , Resultado del Tratamiento , Microambiente Tumoral/inmunología , Aprendizaje Automático no Supervisado , Adulto Joven
13.
Front Immunol ; 12: 670280, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34484175

RESUMEN

Cancer genome sequencing has identified dozens of mutations with a putative role in lymphomagenesis and leukemogenesis. Validation of driver mutations responsible for B cell neoplasms is complicated by the volume of mutations worthy of investigation and by the complex ways that multiple mutations arising from different stages of B cell development can cooperate. Forward and reverse genetic strategies in mice can provide complementary validation of human driver genes and in some cases comparative genomics of these models with human tumors has directed the identification of new drivers in human malignancies. We review a collection of forward genetic screens performed using insertional mutagenesis, chemical mutagenesis and exome sequencing and discuss how the high coverage of subclonal mutations in insertional mutagenesis screens can identify cooperating mutations at rates not possible using human tumor genomes. We also compare a set of independently conducted screens from Pax5 mutant mice that converge upon a common set of mutations observed in human acute lymphoblastic leukemia (ALL). We also discuss reverse genetic models and screens that use CRISPR-Cas, ORFs and shRNAs to provide high throughput in vivo proof of oncogenic function, with an emphasis on models using adoptive transfer of ex vivo cultured cells. Finally, we summarize mouse models that offer temporal regulation of candidate genes in an in vivo setting to demonstrate the potential of their encoded proteins as therapeutic targets.


Asunto(s)
Leucemia de Células B/genética , Linfoma de Células B/genética , Animales , Sistemas CRISPR-Cas/genética , Modelos Animales de Enfermedad , Humanos , Ratones , Mutagénesis Insercional/métodos
14.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(4): 1085-1092, 2021 Aug.
Artículo en Chino | MEDLINE | ID: mdl-34362486

RESUMEN

OBJECTIVE: To investigate the effect and molecular mechanism of miR-142-3p to the proliferation, cycle and apoptosis of acute B lymphocytic leukemia (B-ALL) cells by regulating the homeobox gene 5 (HOXA5) expression. METHODS: Real-time fluorescence quantitative PCR was used to detect the expression levels of miR-142-3p and HOXA5 in human B-ALL cell Nalm6 cell line and human B lymphoblast Hmy2-cir cells. Nalm6 was transfected by using liposome transfection technology, miR-142-3p mimic, pcDNA-HOXA5 overexpression plasmid, miR-142-3p mimic+pcDNA-HOXA5 overexpression plasmid, and control. The binding site of HOXA5 and miR-142-3p was predicted according to microRNA.org, and the targeting relationship between miR-142-3p and HOXA5 gene was detected by double luciferase reporter gene experiment. The effect of miR-142-3p to the proliferation of Nalm6 cells was detected using the Cell Counting Box-8 (CCK-8) method and cell clone formation experiments. Flow cytometry was used to detect the effects of miR-142-3p to cell cycle distribution and apoptosis of Nalm6 cells. The expression levels of cell cycle-related proteins, including G1 /S-specific cyclin-D1 (CyclinD1), Cyclin-dependent kinase 4 (CDK4) and B-cell lymphoma/ leukemia-2 protein (BCL-2), BCL-2 related X protein (Bax), cysteine-aspartate-specific protease (Caspase-3) were detected by Western blot. RESULTS: Compared with Hmy2-cir cells, miR-142-3p showed low expression in Nalm6 cells and HOXA5 showed high expression (P<0.05). MiR-142-3p and HOXA5 3'-UTR showed complementary binding regions, the luciferase activity of miR-142-3p mimic and wild-type HOXA5 3'-UTR was significantly lower than that of miR-142-3p negative control and wild-type HOXA5 3'-UTR (P<0.05). The proliferation of Nalm6 cells and the number of cell clones could be inhibited by miR-142-3p mimic after 48 and 72 hours of transfection (P<0.05), which causing G1 phase arrest of Nalm6 cells and inhibiting the expression of CyclinD1 and CDK4 protein (P<0.01), promoting the apoptosis of Nalm6 cells, and inhibiting the expression of BCL-2 protein, moreover, promoting the expression of Bax and Caspase-3 protein (P<0.05). CONCLUSION: MiR-142-3p can inhibit the proliferation of Nalm6 cells by targeting down-regulation the expression of HOXA5, arrest the G1 phase of cells, and promote apoptosis of the cells.


Asunto(s)
Leucemia de Células B , MicroARNs , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Genes Homeobox , Proteínas de Homeodominio/genética , Humanos , Leucemia de Células B/genética , MicroARNs/genética
16.
Biochem Biophys Res Commun ; 565: 72-78, 2021 08 06.
Artículo en Inglés | MEDLINE | ID: mdl-34098314

RESUMEN

A better understanding of cell-intrinsic factors involved in regulating stem cells and cancer cells will help advance stem cell applications and cancer cell treatment. Previously, we showed that leukocyte immunoglobulin-like receptor B2 (LILRB2) and its mouse ortholog, paired immunoglobulin-like receptor B (PIRB), promote blood stem cell and leukemia development. Another unique mouse paralog to PIRB called gp49B1 was also discovered. However, the roles of gp49B1 in hematopoietic stem cells and leukemia development are largely unknown. Here, we found that gp49B1 is expressed on LSK cells of mouse neonatal hematopoietic organs and is positively correlated with c-Kit expression. However, in noncompetitive and competitive repopulation assays, neonatal splenic gp49B1-positive and c-Kit-highly expressed LSK cells exhibited poor engraftment potential and lymphoid lineage bias. Moreover, in a mouse N-Myc-induced precursor B-acute lymphoblastic leukemia (pre-B ALL) model, we found that gp49B1 deficiency or low levels of c-Kit led to a delay in leukemia development. Together, our results suggest that gp49B1 expressed on hematopoietic progenitor cells supports hematopoietic and leukemia development.


Asunto(s)
Hematopoyesis/genética , Leucemia de Células B/genética , Glicoproteínas de Membrana/genética , Proteínas Proto-Oncogénicas c-kit/genética , Receptores Inmunológicos/genética , Animales , Femenino , Leucemia de Células B/metabolismo , Leucemia de Células B/patología , Masculino , Glicoproteínas de Membrana/deficiencia , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Proto-Oncogénicas c-kit/metabolismo , Receptores Inmunológicos/deficiencia , Receptores Inmunológicos/metabolismo
17.
Blood ; 138(16): 1391-1405, 2021 10 21.
Artículo en Inglés | MEDLINE | ID: mdl-33974080

RESUMEN

We performed a phase 1 clinical trial to evaluate outcomes in patients receiving donor-derived CD19-specific chimeric antigen receptor (CAR) T cells for B-cell malignancy that relapsed or persisted after matched related allogeneic hemopoietic stem cell transplant. To overcome the cost and transgene-capacity limitations of traditional viral vectors, CAR T cells were produced using the piggyBac transposon system of genetic modification. Following CAR T-cell infusion, 1 patient developed a gradually enlarging retroperitoneal tumor due to a CAR-expressing CD4+ T-cell lymphoma. Screening of other patients led to the detection, in an asymptomatic patient, of a second CAR T-cell tumor in thoracic para-aortic lymph nodes. Analysis of the first lymphoma showed a high transgene copy number, but no insertion into typical oncogenes. There were also structural changes such as altered genomic copy number and point mutations unrelated to the insertion sites. Transcriptome analysis showed transgene promoter-driven upregulation of transcription of surrounding regions despite insulator sequences surrounding the transgene. However, marked global changes in transcription predominantly correlated with gene copy number rather than insertion sites. In both patients, the CAR T-cell-derived lymphoma progressed and 1 patient died. We describe the first 2 cases of malignant lymphoma derived from CAR gene-modified T cells. Although CAR T cells have an enviable record of safety to date, our results emphasize the need for caution and regular follow-up of CAR T recipients, especially when novel methods of gene transfer are used to create genetically modified immune therapies. This trial was registered at www.anzctr.org.au as ACTRN12617001579381.


Asunto(s)
Inmunoterapia Adoptiva/efectos adversos , Linfoma/etiología , Receptores de Antígenos de Linfocitos T/uso terapéutico , Anciano , Elementos Transponibles de ADN , Regulación Neoplásica de la Expresión Génica , Técnicas de Transferencia de Gen , Humanos , Inmunoterapia Adoptiva/métodos , Leucemia de Células B/genética , Leucemia de Células B/terapia , Linfoma/genética , Linfoma de Células B/genética , Linfoma de Células B/terapia , Masculino , Receptores de Antígenos de Linfocitos T/genética , Linfocitos T/metabolismo , Transcriptoma , Transgenes
18.
PLoS One ; 16(5): e0248886, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33945543

RESUMEN

B-cell lymphoproliferative disorders exhibit a diverse spectrum of diagnostic entities with heterogeneous behaviour. Multiple efforts have focused on the determination of the genomic drivers of B-cell lymphoma subtypes. In the meantime, the aggregation of diverse tumors in pan-cancer genomic studies has become a useful tool to detect new driver genes, while enabling the comparison of mutational patterns across tumors. Here we present an integrated analysis of 354 B-cell lymphoid disorders. 112 recurrently mutated genes were discovered, of which KMT2D, CREBBP, IGLL5 and BCL2 were the most frequent, and 31 genes were putative new drivers. Mutations in CREBBP, TNFRSF14 and KMT2D predominated in follicular lymphoma, whereas those in BTG2, HTA-A and PIM1 were more frequent in diffuse large B-cell lymphoma. Additionally, we discovered 31 significantly mutated protein networks, reinforcing the role of genes such as CREBBP, EEF1A1, STAT6, GNA13 and TP53, but also pointing towards a myriad of infrequent players in lymphomagenesis. Finally, we report aberrant expression of oncogenes and tumor suppressors associated with novel noncoding mutations (DTX1 and S1PR2), and new recurrent copy number aberrations affecting immune check-point regulators (CD83, PVR) and B-cell specific genes (TNFRSF13C). Our analysis expands the number of mutational drivers of B-cell lymphoid neoplasms, and identifies several differential somatic events between disease subtypes.


Asunto(s)
Genoma Humano , Leucemia de Células B/genética , Linfoma de Células B/genética , Mutación , Proteína de Unión a CREB/genética , Proteínas de Unión al ADN/genética , Subunidades alfa de la Proteína de Unión al GTP G12-G13/genética , Redes Reguladoras de Genes , Humanos , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , Miembro 14 de Receptores del Factor de Necrosis Tumoral/genética , Factor de Transcripción STAT6/genética , Proteína p53 Supresora de Tumor/genética
20.
J Hematol Oncol ; 14(1): 40, 2021 03 06.
Artículo en Inglés | MEDLINE | ID: mdl-33676527

RESUMEN

B cell receptor (BCR) signaling is involved in the pathogenesis of B cell malignancies. Activation of BCR signaling promotes the survival and proliferation of malignant B cells. Bruton tyrosine kinase (BTK) is a key component of BCR signaling, establishing BTK as an important therapeutic target. Several covalent BTK inhibitors have shown remarkable efficacy in the treatment of B cell malignancies, especially chronic lymphocytic leukemia. However, acquired resistance to covalent BTK inhibitors is not rare in B cell malignancies. A major mechanism for the acquired resistance is the emergence of BTK cysteine 481 (C481)  mutations, which disrupt the binding of covalent BTK inhibitors. Additionally, adverse events due to the off-target inhibition of kinases other than BTK by covalent inhibitors are common. Alternative therapeutic options are needed if acquired resistance or intolerable adverse events occur. Non-covalent BTK inhibitors do not bind to C481, therefore providing a potentially effective option to patients with B cell malignancies, including those who have developed resistance to covalent BTK inhibitors. Preliminary clinical studies have suggested that non-covalent BTK inhibitors are effective and well-tolerated. In this review, we discussed the rationale for the use of non-covalent BTK inhibitors and the preclinical and clinical studies of non-covalent BTK inhibitors in B cell malignancies.


Asunto(s)
Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Antineoplásicos/uso terapéutico , Leucemia de Células B/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Agammaglobulinemia Tirosina Quinasa/genética , Animales , Antineoplásicos/efectos adversos , Humanos , Leucemia de Células B/genética , Modelos Moleculares , Terapia Molecular Dirigida , Mutación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/efectos adversos
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