RESUMO
Assessing minimal residual disease (MRD) in B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) is essential for adjusting therapeutic strategies and predicting relapse. Quantitative polymerase chain reaction (qPCR) is the gold standard for MRD. Alternatively, flow cytometry is a quicker and cost-effective method that typically uses leukaemia-associated immunophenotype (LAIP) or different-from-normal (DFN) approaches for MRD assessment. This study describes an optimized 12-colour flow cytometry antibody panel designed for BCP-ALL diagnosis and MRD monitoring in a single tube. This method robustly differentiated hematogones and BCP-ALL cells using two specific markers: CD43 and CD81. These and other markers (e.g. CD73, CD66c and CD49f) enhanced the specificity of BCP-ALL cell detection. This innovative approach, based on a dual DFN/LAIP strategy with a principal component analysis method, can be used for all patients and enables MRD analysis even in the absence of a diagnostic sample. The robustness of our method for MRD monitoring was confirmed by the strong correlation (r = 0.87) with the qPCR results. Moreover, it simplifies and accelerates the preanalytical process through the use of a stain/lysis/wash method within a single tube (<2 h). Our flow cytometry-based methodology improves the BCP-ALL diagnosis efficiency and MRD management, offering a complementary method with considerable benefits for clinical laboratories.
Assuntos
Citometria de Fluxo , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Humanos , Neoplasia Residual/diagnóstico , Citometria de Fluxo/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Imunofenotipagem/métodos , Masculino , Seguimentos , Feminino , Criança , Tomada de Decisão Clínica , Antígenos CD/análise , Pré-EscolarRESUMO
B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) is enriched for a preB cell phenotype, hinting at a specific vulnerability of this cell stage. Two signaling pathways via the preB cell receptor (preBCR) and the interleukin 7 receptor α (IL-7Rα) chain govern the balance between differentiation and proliferation at this stage and both receptor pathways are routinely altered in human BCP-ALL. Here, we review the immunobiology of both the preBCR as well as the IL-7Rα and analyze the human BCP-ALL spectrum in the light of these signaling complexes. Finally, we present a terminology for preBCR signaling modules that distinguishes a pro-proliferative "phase-I" module from a pro-differentiative "phase-II" module. This terminology might serve as a framework to better address shared oncogenic mechanics of preB cell stage BCP-ALL.
Assuntos
Linfoma de Burkitt , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Receptores de Células Precursoras de Linfócitos B/genética , Receptores de Interleucina-7/metabolismo , Linfócitos B/metabolismo , Interleucina-7/metabolismoRESUMO
Acute paediatric leukaemia is diagnosed and monitored via bone marrow aspirate assessment of blasts as a measure of minimal residual disease. Liquid biopsies in the form of blood samples could greatly reduce the need for invasive bone marrow aspirations, but there are currently no blood markers that match the sensitivity of bone marrow diagnostics. Circulating extracellular vesicles (EVs) represent candidate biomarkers that may reflect the blast burden in bone marrow, and several studies have reported on the utility of EVs as biomarkers for adult haematological malignancies. Increased levels of EVs have been reported for several haematological malignancies, and we similarly report here elevated EV concentrations in plasma from paediatric BCP-ALL patients. Plasma EVs are very heterogeneous in terms of their cellular origin, thus identifying a cancer selective EV-marker is challenging. Here, we undertook a reductionistic approach to identify protein markers selectively associated to plasma EVs derived from BCP-ALL patients. The EV proteome of primary BCP-ALL cell-derived EVs were compared against EVs from healthy donor B cells and the BCP-ALL cell line REH, and further against EVs isolated from plasma of healthy paediatric donors and paediatric BCP-ALL patients. With this approach, we identified a signature of 6 proteins (CD317, CD38, IGF2BP1, PCNA, CSDE1, and GPR116) that were specifically identified in BCP-ALL derived EVs only and not in healthy control EVs, and that could be exploited as diagnostic biomarkers.
Assuntos
Vesículas Extracelulares , Neoplasias Hematológicas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Humanos , Criança , Linfócitos B , Biomarcadores , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Proteínas de Ligação a DNA , Proteínas de Ligação a RNARESUMO
B-cell precursor acute lymphoblastic leukemia (BCP-ALL), the most common childhood cancer, originates from lymphoid precursor cells in bone marrow committed to the B-cell lineage. Environmental factors and genetic abnormalities disturb the normal maturation of these precursor cells, promoting the formation of leukemia cells and suppressing normal hematopoiesis. The underlying mechanisms of progression are unclear, but BCP-ALL incidence seems to be increasing in parallel with the adoption of modern lifestyles. This study hypothesized that air pollution and haze are risk factors for BCP-ALL progression. The current study revealed that indeno(1,2,3-cd)pyrene (IP), a major component of polycyclic aromatic hydrocarbons (PAHs) in air, promotes oncogenic activities (proliferation, transformation, and disease relapse) in vitro and in vivo. Mechanistically, IP treatment activated the aryl hydrocarbon receptor (AHR)-indoleamine-2,3-dioxygenase (IDOs) axis, thereby enhancing tryptophan metabolism and kynurenine (KYN) level and consequent promoting the KYN-AHR feedback loop. IP treatment decreased the time to disease relapse and increased the BCP-ALL cell count in an orthotopic xenograft mouse model. Additionally, in 50 clinical BCP-ALL samples, AHR and IDO were co-expressed in a disease-specific manner at mRNA and protein levels, while their mRNA levels showed a significant correlation with disease-free survival duration. These results indicated that PAH/IP exposure promotes BCP-ALL disease progression.
Assuntos
Neoplasias , Hidrocarbonetos Policíclicos Aromáticos , Humanos , Camundongos , Animais , Cinurenina/metabolismo , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismoRESUMO
BACKGROUND: Myeloid cell leukemia-1 (MCL-1) is a component of the Bcl-2 anti-apoptotic family that plays a key role in cell proliferation and differentiation. Despite tremendous improvements toward identification of the role of MCL-1 in leukemia progression, the functional significance and molecular mechanism behind the effect of MCL-1 overexpression on the proliferation of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has not been clarified. In addition, less well appreciated is the effect of MCL-1 inhibition on the potentiation of doxorubicin-induced apoptosis in BCP-ALL cell lines. In the present study, we aimed to shed light on the anti-cancer properties of S63845, a potent Mcl-1 inhibitor, in BCP-ALL cell lines either alone or in combination with a chemotherapeutic drug. METHODS AND RESULTS: Mononuclear cells from patients with Pre-B ALL and BCP-ALL cell lines were treated with S63845 in presence or absence of doxorubicin, induction of apoptosis was evaluated using Annexin-V/PI staining kit. mRNA and protein expression levels were assessed by qRT-PCR and western blot analysis, respectively. Our results declared that inhibition of Mcl-1 impairs cell growth and induces apoptosis in pre-B ALL cells through activation of caspase-3 and up-regulation of a repertoire of pro-apoptotic Bcl-2 family. Additionally, S63845 acts synergically with doxorubicin to induce apoptosis in BCP-ALL cell lines. CONCLUSIONS: Our data declared that MCL-1 inhibition alone or in combination with a chemotherapeutic agent is considered an appealing strategy for the induction of apoptosis in BCP-ALL cells.
Assuntos
Doxorrubicina , Leucemia-Linfoma Linfoblástico de Células Precursoras , Apoptose , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Humanos , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismoRESUMO
BACKGROUND: The stability of the housekeeping gene (HKG) expression is an absolute prerequisite for accurate normalization of target gene expression in a quantitative real-time polymerase chain reaction (RQ-PCR). In RQ-PCR, the widely used normalization approach involves the standardization of target genes to the most stable HKG control genes. According to the recent literature, in different experimental conditions the HKGs exhibit either up or down-regulation and thus affecting the gene expression profiles of target genes which leads to erroneous results. This implies that it is very important to select the appropriate HKG and verify the expression stability of the HKG before quantification of the target gene. METHODS AND RESULTS: The present study aims to analyze six different HKGs for their expression profiles and stability in BCR-ABL1 negative cases and validate them in BCR-ABL1 positive cases, detected by multiplex reverse transcribed polymerase chain reaction (RT-PCR). Six commonly used reference genes (GAPDH, ABL1, RNA18S, ACTB, GUSB, and EEF2) were selected in this study. RQ-PCR was performed on 24 BCR-ABL1 negative cases and the outcomes were validated on 24 BCR-ABL1 positive cases. RefFinder™, a web-based composite software was used to check the stability of HKG genes by different algorithms and comprehensive ranking of each HKG gene in BCR-ABL1 negative cases and finally validated in BCR-ABL1 positive cases. CONCLUSIONS: It was found that RNA18S, ABL1 and GUSB are good stable HKG genes, which showed minimum variability in gene expression compared to GAPDH, EEF2, and ACTB, the most commonly used HKG.
Assuntos
Genes Essenciais , Leucemia-Linfoma Linfoblástico de Células Precursoras , Proteínas de Fusão bcr-abl/genética , Expressão Gênica , Genes Essenciais/genética , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Reação em Cadeia da Polimerase em Tempo Real/métodos , Padrões de ReferênciaRESUMO
Most B cell precursor acute lymphoblastic leukemia (BCP ALL) can be classified into known major genetic subtypes, while a substantial proportion of BCP ALL remains poorly characterized in relation to its underlying genomic abnormalities. We therefore initiated a large-scale international study to reanalyze and delineate the transcriptome landscape of 1,223 BCP ALL cases using RNA sequencing. Fourteen BCP ALL gene expression subgroups (G1 to G14) were identified. Apart from extending eight previously described subgroups (G1 to G8 associated with MEF2D fusions, TCF3-PBX1 fusions, ETV6-RUNX1-positive/ETV6-RUNX1-like, DUX4 fusions, ZNF384 fusions, BCR-ABL1/Ph-like, high hyperdiploidy, and KMT2A fusions), we defined six additional gene expression subgroups: G9 was associated with both PAX5 and CRLF2 fusions; G10 and G11 with mutations in PAX5 (p.P80R) and IKZF1 (p.N159Y), respectively; G12 with IGH-CEBPE fusion and mutations in ZEB2 (p.H1038R); and G13 and G14 with TCF3/4-HLF and NUTM1 fusions, respectively. In pediatric BCP ALL, subgroups G2 to G5 and G7 (51 to 65/67 chromosomes) were associated with low-risk, G7 (with ≤50 chromosomes) and G9 were intermediate-risk, whereas G1, G6, and G8 were defined as high-risk subgroups. In adult BCP ALL, G1, G2, G6, and G8 were associated with high risk, while G4, G5, and G7 had relatively favorable outcomes. This large-scale transcriptome sequence analysis of BCP ALL revealed distinct molecular subgroups that reflect discrete pathways of BCP ALL, informing disease classification and prognostic stratification. The combined results strongly advocate that RNA sequencing be introduced into the clinical diagnostic workup of BCP ALL.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras B/classificação , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Transcriptoma , Adulto , Criança , Bases de Dados de Ácidos Nucleicos , Feminino , Humanos , Masculino , Modelos Genéticos , Mutação , Fusão Oncogênica , Proteínas de Fusão Oncogênica/genética , Prognóstico , Análise de Sequência de RNARESUMO
Second mitochondria-derived activator of caspase (SMAC) mimetics (SMs) targeting inhibitor of apoptosis proteins (IAPs) activate cell death pathways, and are currently being evaluated in clinical trials. Their successful therapeutic implementation requires upfront identification of patients who could benefit from a SM-based treatment but biomarkers for SM sensitivity have not yet been described. Here, we analyzed the intrinsic activity of two monovalent (AT406 and LCL161) and two bivalent (Birinapant and BV6) SMs on unselected patient-derived pediatric precursor B-cell acute lymphoblastic leukemia (BCP-ALL) identifying a subset of patient samples to be particularly sensitive to SM-induced cell death. This subset was defined by a characteristic gene expression signature with 127 differentially regulated genes, amongst them TNFRSF1A encoding TNFR1, and a critical role of TNFR1 in SM-induced cell death in sensitive BCP-ALL was confirmed on the functional level. Interestingly, samples with intermediate or low sensitivity to SMs were sensitized to SM-induced cell death by inhibition of caspases using zVAD.fmk or Emricasan, a pan-caspase inhibitor in clinical trials. When we compared our expression data to published data sets, we identified an overlap of four genes to be commonly differentially regulated in SM-sensitive BCP-ALL, that is, TSPAN7, DIPK1C, MTX2 and, again, TNFRSF1A. Functional testing revealed that this set of genes identified samples with high sensitivity to SM treatment. In summary, our data suggest using this gene signature as biomarker predicting response to SM treatment and point to the development of new combinatorial treatments consisting of SMs and pan-caspase inhibitors for a successful clinical implementation of SMs in treatment of BCP-ALL.
Assuntos
Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Azocinas/farmacologia , Compostos Benzidrílicos/farmacologia , Dipeptídeos/farmacologia , Indóis/farmacologia , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Proteínas Mitocondriais/antagonistas & inibidores , Oligopeptídeos/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Tiazóis/farmacologia , Animais , Apoptose/efeitos dos fármacos , Inibidores de Caspase/farmacologia , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Células Precursoras de Linfócitos B/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Despite progress in treating B-cell precursor acute lymphoblastic leukemia (BCP-ALL), disease recurrence remains the main cause of treatment failure. New strategies to improve therapeutic outcomes are needed, particularly in high-risk relapsed patients. Che-1/AATF (Che-1) is an RNA polymerase II-binding protein involved in proliferation and tumor survival, but its role in hematological malignancies has not been clarified. Here, we show that Che-1 is overexpressed in pediatric BCP-ALL during disease onset and at relapse, and that its depletion inhibits the proliferation of BCP-ALL cells. Furthermore, we report that c-Myc regulates Che-1 expression by direct binding to its promoter and describe a strict correlation between Che-1 expression and c-Myc expression. RNA-seq analyses upon Che-1 or c-Myc depletion reveal a strong overlap of the respective controlled pathways. Genomewide ChIP-seq experiments suggest that Che-1 acts as a downstream effector of c-Myc. These results identify the pivotal role of Che-1 in the control of BCP-ALL proliferation and present the protein as a possible therapeutic target in children with relapsed BCP-ALL.
Assuntos
Proteínas Reguladoras de Apoptose/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Repressoras/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Proteínas de Ligação a DNA/genética , Regulação Leucêmica da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Regiões Promotoras Genéticas/genéticaRESUMO
Our study aimed to determine the expression pattern and clinical relevance of CD99 in paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). Our findings demonstrate that high expression levels of CD99 are mainly found in high-risk BCP-ALL, e.g. BCR-ABL1 and CRLF2Re/Hi, and that high CD99 mRNA levels are strongly associated with a high frequency of relapse, high proportion of positive for minimal residual disease at day 29 and poor overall survival in paediatric cohorts, which indicate that CD99 is a potential biomarker for BCP-ALL.
Assuntos
Antígeno 12E7/biossíntese , Biomarcadores Tumorais/biossíntese , Regulação Leucêmica da Expressão Gênica , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Antígeno 12E7/genética , Adolescente , Biomarcadores Tumorais/genética , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Lactente , Masculino , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Receptores de Citocinas/genética , Receptores de Citocinas/metabolismo , Taxa de Sobrevida , Adulto JovemRESUMO
BACKGROUND: The outcome of approximately 20% of patients with acute lymphoblastic leukemia (ALL) remains poor because of disease recurrence. We examined whether DNA methylation of cadherin superfamily genes is a useful biomarker for ALL relapse. PROCEDURE: We used Infinium Methylation 450K Arrays to assess genome-wide DNA methylation status. The methylation status of each individual gene was then determined by a combination of bisulfite restriction analysis and genome bisulfite sequencing. mRNA expression was evaluated by reverse-transcriptase PCR (RT-PCR) and quantitative real-time PCR. RESULTS: Cadherin superfamily genes including cadherin (CDH) 1, protocadherin (PCDH) 8, and PCDH17 were selected for analysis of methylation status. In 40 patient samples with B-cell precursor (BCP) ALL at diagnosis, the methylation frequencies of CDH1, PCDH8, and PCDH17 were 62.5, 55, and 30%, respectively. CDH1 and PCDH8 methylation was also detected in 80 and 20% of control bone marrow (BM) samples, respectively. On the contrary, PCDH17 was unmethylated in all control BM samples. There was a significant correlation between the methylation status of PCDH17 (but not CDH1 and PCDH8) and event-free survival or overall survival. Univariate and multivariate analyses showed that only PCDH17 methylation was associated with an increased risk for relapse and mortality in patients with BCP ALL. CONCLUSION: PCDH17 methylation at diagnosis was closely related to poor prognosis and thus could be used as a new biomarker to predict relapse in patients with BCP ALL.
Assuntos
Biomarcadores Tumorais/genética , Caderinas/genética , Metilação de DNA , Recidiva Local de Neoplasia/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Antígenos CD , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Masculino , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico , Regiões Promotoras Genéticas/genética , Protocaderinas , Reação em Cadeia da Polimerase em Tempo Real , Taxa de SobrevidaAssuntos
Evolução Clonal/genética , Rearranjo Gênico , Cadeias Pesadas de Imunoglobulinas/genética , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Biomarcadores Tumorais , Biópsia , Medula Óssea/metabolismo , Aberrações Cromossômicas , Progressão da Doença , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunofenotipagem/métodos , Pessoa de Meia-Idade , Neoplasia Residual/diagnósticoRESUMO
Over the last 20-30 years CD19 has gained attention as a potential target in the therapy of B-cell malignancies. In particular, targeting CD19 with the bispecific T-cell engager (BiTE) antibody Blinatumomab and T-cells modified by chimeric antigen receptors (CAR) has shown promising efficacy in early phase clinical trials for adults and children with precursor B-cell ALL (BCP-ALL). This review will discuss the rationale behind targeting CD19 in BCP-ALL and its potential importance in BCP-ALL signaling pathways.
Assuntos
Anticorpos Biespecíficos/farmacologia , Antígenos CD19/imunologia , Antineoplásicos/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Adulto , Antígenos CD19/química , Ensaios Clínicos como Assunto , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologiaRESUMO
MYC and BCL2 translocations in B-cell lymphomas are defined as "double-hit" associated with poor prognosis in adult patients. Such double-hit events are extremely rare in B-cell precursor acute lymphoblastic leukemia (BCP-ALL), especially in pediatric patients or young adults. This study is to investigate the clinical manifestation of de novo MYCyBCL2 double-hit BCP-ALL in young patients. Two pediatric and one young adult patients were identified after a retrospective data review and all without previous history of lymphoma. There were two females and one male aged 15, 18, and 24, respectively. All patients had an unremarkable medical history before presenting with extensive bone marrow and central nervous system involvement at diagnosis. Flow cytometry immunophenotypic analysis showed an immature B-cell immunophenotype (CD10+, CD19+, TdT+, surface Ig-) and immunohistochemistry showed high expression of MYC and BCL2 in all cases. All patients showed complex karyotypes associated with 8q24 abnormalities in the form of t(8;9)(q24;p13) or t(8;14)(q24;q32) and t(14;18)(q32;q21) and fluorescence in situ hybridization confirmed MYC and BCL2 rearrangements. Two patients died of refractory disease or disease progression 7 and 13 months after initial diagnosis, respectively, and the third patient was treated with protocol AALL0232 under the Children's Oncology Group study, achieved complete remission and remained in remission for 53 months at last follow-up. Our study showed that De novo MYCyBCL2 double-hit BCP-ALL is a rare disease that also occurs in pediatric and young adult patients and associated with complex karyotypes and poor prognosis. Younger patients may benefit from intensified chemotherapy.
Assuntos
Cromossomos Humanos/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-myc/genética , Translocação Genética , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Feminino , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Prognóstico , Estudos RetrospectivosRESUMO
Acute lymphoblastic leukaemia (ALL) is the most prevalent cancer in children, and excessive iron buildup resulting from blood transfusions and chemotherapy potentially has a negative impact on treatment outcomes and prognosis in patients with ALL. Therefore, initiating early iron chelation therapy during ALL treatment is a logical approach. Ideally, the selected iron chelator should also possess anti-leukaemia properties. The aim of the present study was to explore the potential impact and underlying mechanism of deferasirox (DFX) in ALL therapy. This study proved that DFX, an iron chelator, is capable of inducing leukaemia cell death through ferroptosis, which is achievable by increasing the expression of acetylated nuclear factor erythroid 2-related factor 2 (NRF2). More specifically, NRF2 acetylation on Lys599 was facilitated by acetyltransferase-p300/CBP. These findings indicate that DFX could serve as a potent adjunctive medication for patients with ALL. Moreover, DFX may offer dual benefits in ALL treatment, functioning as both an iron chelator and NRF2-modulating agent. Further research and clinical trials are necessary to fully elucidate the therapeutic potential of DFX in patients with ALL and incorporate it into treatment protocols.
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Natural killer (NK) cells are important for early tumor immune surveillance. In patients with hematological cancers, NK cells are generally functional deficient and display dysregulations in their receptor repertoires. Acute leukemia is the most common cancer in children, and we here performed a comparative phenotypic profiling of NK cells from B-cell precursor acute lymphoblastic leukemia (BCP-ALL) patients to identify aberrant NK cell phenotypes. NK cell phenotypes, maturation, and function were analyzed in matched bone marrow and blood NK cells from BCP-ALL patients at diagnosis, during treatment, and at end of treatment and compared with age-matched pediatric control subjects. Expression of several markers were skewed in patients, but with large interindividual variations. Undertaking a multiparameter approach, we found that high expression levels of NKG2A was the single predominant marker distinguishing NK cells in BCP-ALL patients compared with healthy control subjects. Moreover, naïve CD57-NKG2A NK cells dominated in BCP-ALL patients at diagnosis. Further, we found dysregulated expression of the activating receptor DNAM-1 in resident bone marrow CXCR6+ NK cells. CXCR6+ NK cells lacking DNAM-1 expressed NKG2A and had a tendency for lower degranulation activity. In conclusion, high expression of NKG2A dominates NK cell phenotypes from pediatric BCP-ALL patients, indicating that NKG2A could be targeted in therapies for this patient group.
Assuntos
Células Matadoras Naturais , Leucemia Mieloide Aguda , Humanos , Criança , Fenótipo , Biomarcadores/metabolismo , Subfamília C de Receptores Semelhantes a Lectina de Células NKRESUMO
The IKZF1 gene encodes a transcription factor that belongs to the family of zinc-finger DNA-binding proteins associated with chromatin remodeling. The protein product, IKAROS, had been proved to regulate lymphopoiesis. Subsequent mouse model studies have further confirmed its regulating role in lymphopoiesis as well as in hematopoiesis; besides, it associates with immune function, certain immune disorders like common variable immunodeficiency and dysgammaglobulinemia have been proved to be associated with germline IKZF1 mutations. Dysfunction of IKAROS also bears paramount significance in leukemic transformation and alterations of IKZF1 gene predicts a poor prognosis in hematological malignancies. As an independent prognostic marker, IKZF1 has been incorporated in the risk stratification of BCP-ALL and stratification-guided therapy has also been generated. In this review, we provide a concise and comprehensive overview on the multifaceted roles of IKZF1 gene.
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BACKGROUND: Enhancer reprogramming plays a significant role in the heterogeneity of cancer. However, we have limited knowledge about the impact of chromatin remodeling in B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) patients, and how it affects tumorigenesis and drug response. Our research focuses on investigating the role of enhancers in sustaining oncogenic transformation in children with BCP-ALL. METHODS: We used ATAC-seq to study the accessibility of chromatin in pediatric BCP-ALL at three different stages-onset, remission, and relapse. Using a combination of computational and experimental methods, we were able to analyze the accessibility landscape and focus on the most significant cis-regulatory sites. These sites were then functionally validated through the use of Promoter capture Hi-C in a primary cell line model called LAL-B, followed by RNA-seq and genomic deletion of target sites using CRISPR-Cas9 editing. RESULTS: We found that enhancer activity changes during cancer progression and is mediated by the production of enhancer RNAs (eRNAs). CRISPR-Cas9-mediated validation of previously unknown eRNA productive enhancers demonstrated their capability to control the oncogenic activities of the MYB and DCTD genes. CONCLUSIONS: Our findings directly support the notion that productive enhancer engagement is a crucial determinant of the BCP-ALL and highlight the potential of enhancers as therapeutic targets in pediatric BCP-ALL.
Assuntos
Transformação Celular Neoplásica , Progressão da Doença , Elementos Facilitadores Genéticos , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , CriançaRESUMO
BACKGROUND: A prospective evaluation of non-alcoholic fatty liver disease (NAFLD) during induction therapy for acute lymphoblastic leukemia (ALL) has not been performed. Herein, we prospectively investigated the frequency, risk factors, and outcomes of NAFLD during induction therapy in children and adolescents with B-cell precursor ALL (BCP-ALL). METHODS: This study enrolled 74 newly diagnosed BCP-ALL cases aged 1 year and older who were admitted to our department between January 2011 and December 2020. Median age was 6.6 years (1.3-17.5 years). Plain computed tomography (CT) of the upper abdomen was performed before induction therapy, and on days 15 and 29 after initiation of induction therapy. Patients with a liver/spleen CT ratio <0.9 were defined as having NAFLD. RESULTS: The frequency of NAFLD was 73%. Patients with NAFLD had a higher rate of hypertriglyceridemia. There was no significant difference in 5-year overall survival and event-free survival (EFS) between patients with and without NAFLD. However, after restricting the target age to 10 years and older, 5-year EFS was significantly higher in patients with NAFLD than in those without (88.5 vs. 42.9%, respectively, P = 0.037). Similarly, 5-year cumulative incidence of relapse (CIR) was significantly lower in patients with NAFLD than in those without it (5-year CIR, 6.3 vs. 57.1%, respectively, P = 0.013). CONCLUSION: Patients with NAFLD exhibit better outcomes including 5-year EFS and CIR. Further studies are necessary.
Assuntos
Hepatopatia Gordurosa não Alcoólica , Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Humanos , Adolescente , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Intervalo Livre de Doença , Prognóstico , Quimioterapia de Indução , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , RecidivaRESUMO
BACKGROUND/AIM: In precursor B-cell lineage acute lymphoblastic leukemia (BCP-ALL), leukemic cells harbor genetic abnormalities that play an important role in the diagnosis, prognosis, and treatment. A subgroup of BCP-ALL is characterized by the presence of a Philadelphia (Ph) chromosome and a chimeric BCR::ABL1 gene, whereas in another subgroup, leukemic cells exhibit near-haploidy with chromosome number 24-30. This study presents the third documented case of BCP-ALL in which a near haploid clone concurrently displayed a Ph chromosome/BCR::ABL1. CASE REPORT: Bone marrow cells obtained at diagnosis from a 25-year-old man with BCP-ALL were genetically investigated using G-banding, fluorescence in situ hybridization, and array comparative genomic hybridization. Leukemic cells had an abnormal karyotype 28