RESUMO

BACKGROUND: A lower dosage of tyrosine kinase inhibitors (TKIs) in patients with chronic myeloid leukaemia (CML) has shown efficacy in managing short-term toxicity and maintaining a deep molecular response in patients who fail to achieve treatment-free remission. METHOD: From over 700 patients with CML who were treated at two centres over the last three decades, this retrospective study identified eight patients characterised by long-term treatment failure and simultaneous prolonged significant haematologic toxicity that prevented the use of the standard tyrosine kinase inhibitor dosage. RESULTS: Patients had a high or intermediate ELTS risk score, and most had significant comorbidities. Two patients were treated previously with busulfan, and four were aged over 70, which might explain the reduced pool of normal haematopoietic stem cells. However, concomitant myelodysplastic syndrome or the presence of clonal haematopoiesis of indeterminate potential was not demonstrated. Despite prolonged treatment failure, the survival of these patients (who were ineligible for stem cell transplantation) ranged from 45-396 months. Neither mutations in the ABL kinase domain nor additional cytogenetic abnormalities developed during the treatment of these patients, prompting speculation about the low selective pressure of low-dose tyrosine kinase inhibitors and/or the absence of mutations at diagnosis. CONCLUSION: It is important not to stop treatment with tyrosine kinase inhibitors at a low personalised dosage in CML patients with prolonged significant haematologic toxicity despite long-term treatment failure.

RESUMO

The present study analyses the clinical characteristics of patients diagnosed with cutaneous fusarium through a systematic review of cases reported in literature. A total of 39 cases were included, of which 53% were men, 30% were women, and in 17% the sex was not specified. The age ranged from 5 to 85 years. Most cases were reported in Brazil, followed by Japan and United States of America. The most common agent was Fusarium solani, in 37.5% of the patients. Most of the affected individuals had acute myeloid leukaemia and some of the predisposing factors, which included induction chemotherapy, febrile neutropenia, and bone marrow transplantation. The clinical topography of the lesions was located in 27.5% and disseminated in 72.5%, with the most observed clinical feature outstanding the presence of papules and nodules with central necrosis in 47% of the cases. Longer survival was demonstrated in those treated with more than three antifungals. It is concluded that cutaneous fusarium is a complex and challenging clinical entity, infection in patients with leukaemias underscores the need for thorough care to decrease morbidity and mortality.

Assuntos

Antifúngicos , Fusariose , Fusarium , Humanos , Fusariose/tratamento farmacológico , Fusariose/microbiologia , Fusarium/isolamento & purificação , Idoso , Adulto , Antifúngicos/uso terapêutico , Pessoa de Meia-Idade , Feminino , Masculino , Idoso de 80 Anos ou mais , Adulto Jovem , Adolescente , Brasil/epidemiologia , Criança , Japão/epidemiologia , Pré-Escolar , Leucemia Mieloide Aguda/complicações , Estados Unidos/epidemiologia , Leucemia/complicações , Leucemia/microbiologia , Dermatomicoses/microbiologia , Dermatomicoses/epidemiologia , Dermatomicoses/tratamento farmacológico , Dermatomicoses/patologia

RESUMO

Acute lymphoblastic leukaemia is currently treated with bacterial L-asparaginase; however, its side effects raise the need for the development of improved and efficient novel enzymes. Previously, we obtained low anti-asparaginase antibody production and high serum enzyme half-life in mice treated with the P40S/S206C mutant; however, its specific activity was significantly reduced. Thus, our aim was to test single mutants, S206C and P40S, through in vitro and in vivo assays. Our results showed that the drop in specific activity was caused by P40S substitution. In addition, our single mutants were highly stable in biological environment simulation, unlike the double-mutant P40S/S206C. The in vitro cell viability assay demonstrated that mutant enzymes have a higher cytotoxic effect than WT on T-cell-derived ALL and on some solid cancer cell lines. The in vivo assays were performed in mice to identify toxicological effects, to evoke immunological responses and to study the enzymes' pharmacokinetics. From these tests, none of the enzymes was toxic; however, S206C elicited lower physiological changes and immune/allergenic responses. In relation to the pharmacokinetic profile, S206C exhibited twofold higher activity than WT and P40S two hours after injection. In conclusion, we present bioengineered E. coli asparaginases with high specific enzyme activity and fewer side effects.

Assuntos

Asparaginase , Escherichia coli , Animais , Asparaginase/genética , Asparaginase/metabolismo , Escherichia coli/genética , Camundongos , Humanos , Mutação , Linhagem Celular Tumoral , Feminino , Sobrevivência Celular/efeitos dos fármacos , Inflamação/genética

RESUMO

BACKGROUND: Acute myeloid leukaemia (AML) is considered a costly disease. Depending on the risk stratification, the patient may receive consolidation with cycles of intermediate doses of cytarabine, auto-HSCT or allo-HSCT according to availability in each service and the availability of a compatible donor. Literature data indicate that safety and effectiveness do not differ between consolidation therapy with intermediate-dose cytarabine or auto-HSCT, and so the cost can help physicians and health managers in their choice. METHOD: The cost of the second consolidation was compared in 18 to 60-year-old patients with de novo AML who were included in the International Consortium of Acute Myeloid Leukaemia (ICAML) protocol. Patients treated with auto-HSCT or intermediate doses of cytarabine (IDAC) were analysed during four years using the microcosting methodology. RESULTS: The mean costs for auto-HSCT and IDAC were BRL$ 34,900.95 (range: 23,611.36-41,229.59) and 15,231.64 (range: 6,546.36-23,253.53), respectively. The mean duration of in-hospital stay was 88.4 (93-133) and 94 (50-153) days, respectively. The mean cost of the four cycles of treatment was BRL$ 114.212,78 for auto-HSCT and BRL$ 121.980,93 for the chemotherapy group. Regardless of the type of treatment, the input that had the greatest economic impact was hospital admission, mainly due to infections. CONCLUSION: Auto-HSCT had a lower average cost per patient and hospitalization rate than chemotherapy.

RESUMO

Despite advancements in utilizing genetic markers to enhance acute myeloid leukaemia (AML) outcome prediction, significant disease heterogeneity persists, hindering clinical management. To refine survival predictions, we assessed the transcriptome of non-acute promyelocytic leukaemia chemotherapy-treated AML patients from five cohorts (n = 975). This led to the identification of a 4-gene prognostic index (4-PI) comprising CYP2E1, DHCR7, IL2RA and SQLE. The 4-PI effectively stratified patients into risk categories, with the high 4-PI group exhibiting TP53 mutations and cholesterol biosynthesis signatures. Single-cell RNA sequencing revealed enrichment for leukaemia stem cell signatures in high 4-PI cells. Validation across three cohorts (n = 671), including one with childhood AML, demonstrated the reproducibility and clinical utility of the 4-PI, even using cost-effective techniques like real-time quantitative polymerase chain reaction. Comparative analysis with 56 established prognostic indexes revealed the superior performance of the 4-PI, highlighting its potential to enhance AML risk stratification. Finally, the 4-PI demonstrated to be potential marker to reclassified patients from the intermediate ELN2017 category to the adverse category. In conclusion, the 4-PI emerges as a robust and straightforward prognostic tool to improve survival prediction in AML patients.

Assuntos

Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/diagnóstico , Masculino , Feminino , Prognóstico , Pessoa de Meia-Idade , Biomarcadores Tumorais/genética , Adulto , Idoso , Transcriptoma , Adolescente , Criança

RESUMO

BACKGROUND: Increased malignancy frequency is well documented in adult-systemic lupus erythematosus (SLE), but with limited reports in childhood-onset SLE (cSLE) series. We explored the frequency of malignancy associated with cSLE, describing clinical and demographic characteristics, disease activity and cumulative damage, by the time of malignancy diagnosis. METHOD: A retrospective case-notes review, in a nationwide cohort from 27 Pediatric Rheumatology centres, with descriptive biopsy-proven malignancy, disease activity/damage accrual, and immunosuppressive treatment were compiled in each participating centre, using a standard protocol. RESULTS: Of the 1757 cSLE cases in the updated cohort, 12 (0.7%) developed malignancy with median time 10 years after cSLE diagnosis. There were 91% females, median age at cSLE diagnosis 12 years, median age at malignancy diagnosis 23 years. Of all diagnosed malignancies, 11 were single-site, and a single case with concomitant multiple sites; four had haematological (0.22%) and 8 solid malignancy (0.45%). Median (min-max) SLEDAI-2 K scores were 9 (0-38), median (min-max) SLICC/ACR-DI (SDI) score were 1 (1-5) Histopathology defined 1 Hodgkin's lymphoma, 2 non-Hodgkin's lymphoma, 1 acute lymphoblastic leukaemia; 4 gastrointestinal carcinoma, 1 squamous cell carcinoma of the tongue and 1 anal carcinoma; 1 had sigmoid adenocarcinoma and 1 stomach carcinoid; 3 had genital malignancy, being 1 vulvae, 1 cervix and 1 vulvae and cervix carcinomas; 1 had central nervous system oligodendroglioma; and 1 testicle germ cell teratoma. CONCLUSION: Estimated malignancy frequency of 0.7% was reported during cSLE follow up in a multicentric series. Median disease activity and cumulative damage scores, by the time of malignancy diagnoses, were high; considering that reported in adult series.

Assuntos

Carcinoma , Lúpus Eritematoso Sistêmico , Criança , Feminino , Humanos , Masculino , Adulto Jovem , Idade de Início , Carcinoma/complicações , Lúpus Eritematoso Sistêmico/complicações , Estudos Retrospectivos

RESUMO

OBJECTIVES: We aimed to investigate an outbreak of vancomycin-resistant Enterococcus faecium (VREfm) in paediatric patients from Hospital Pequeno Príncipe. The susceptibility profile was determined, and whole-genome sequencing (WGS) was used to analyse the genetic context of the strains. METHODS: Five VREfm isolates were recovered from sterile sites and surveillance cultures of two paediatric patients with acute lymphoblastic leukaemia. Species identification was performed using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS), and the minimum inhibitory concentration (MIC) was assessed according to the European Committee for Antimicrobial Susceptibility Testing (EUCAST). WGS was performed to analyse the genetic context of virulence and resistance genes, and in silico multilocus sequence typing was performed to identify the sequence typing of the strains. RESULTS: High-level vancomycin resistance was observed in all isolates (≥256 mg/L). WGS revealed the presence of mobile genetic elements, such as plasmids (rep2, rep11a, repUS15, rep17, and rep18a), insertion sequences, and phages. Multiple resistance genes (aac(6')-aph(2"), dfrG, ermB, and vanA) and virulence genes (acm and efaAfm) were identified. All the isolates were assigned to ST117 (ST1133 - via a novel MLST), an important epidemic lineage associated with nosocomial infections and outbreaks. CONCLUSION: Our results show that the ST117 (ST1133) VREfm isolates are circulating in paediatric patients, which raises a great concern. The development of new drugs as well as the implementation of an antimicrobial stewardship program are necessary for their correct management, limiting the spread of resistance in oncohematological patients.

Assuntos

Enterococcus faecium , Leucemia-Linfoma Linfoblástico de Células Precursoras , Enterococos Resistentes à Vancomicina , Humanos , Criança , Vancomicina/farmacologia , Tipagem de Sequências Multilocus , Brasil/epidemiologia , Genótipo , Enterococos Resistentes à Vancomicina/genética , Surtos de Doenças

RESUMO

Abstract Background Increased malignancy frequency is well documented in adult-systemic lupus erythematosus (SLE), but with limited reports in childhood-onset SLE (cSLE) series. We explored the frequency of malignancy associated with cSLE, describing clinical and demographic characteristics, disease activity and cumulative damage, by the time of malignancy diagnosis. Method A retrospective case-notes review, in a nationwide cohort from 27 Pediatric Rheumatology centres, with descriptive biopsy-proven malignancy, disease activity/damage accrual, and immunosuppressive treatment were compiled in each participating centre, using a standard protocol. Results Of the 1757 cSLE cases in the updated cohort, 12 (0.7%) developed malignancy with median time 10 years after cSLE diagnosis. There were 91% females, median age at cSLE diagnosis 12 years, median age at malignancy diagnosis 23 years. Of all diagnosed malignancies, 11 were single-site, and a single case with concomitant multiple sites; four had haematological (0.22%) and 8 solid malignancy (0.45%). Median (min-max) SLEDAI-2 K scores were 9 (0-38), median (min-max) SLICC/ACR-DI (SDI) score were 1 (1-5) Histopathology defined 1 Hodgkin's lymphoma, 2 non-Hodgkin's lymphoma, 1 acute lymphoblastic leukaemia; 4 gastrointestinal carcinoma, 1 squamous cell carcinoma of the tongue and 1 anal carcinoma; 1 had sigmoid adenocarcinoma and 1 stomach carcinoid; 3 had genital malignancy, being 1 vulvae, 1 cervix and 1 vulvae and cervix carcinomas; 1 had central nervous system oligodendroglioma; and 1 testicle germ cell teratoma. Conclusion Estimated malignancy frequency of 0.7% was reported during cSLE follow up in a multicentric series. Median disease activity and cumulative damage scores, by the time of malignancy diagnoses, were high; considering that reported in adult series.

RESUMO

AIM: We evaluated fine motor skills; precision, motor integration, manual dexterity, and upper-limb coordination according to sex and risk stratification in children with Acute Lymphoblastic Leukaemia (ALL). METHODS: We evaluated twenty-nine children in the maintenance phase aged 6 to 12 years with the Bruininks-Oseretsky Test of Motor Proficiency-second edition (BOT-2), and sex and age-specific norm values of BOT-2 were used to compare our results. RESULTS: We found lower scores on the upper-limb coordination subtest, p = 0.003 and on the manual coordination composite, p = 0.008, than normative values. Most boys performed "average" on both the subtests and the composites, but girls showed lower scores with a mean difference of 7.69 (95%CI; 2.24 to 3.14), p = 0.009. Girls' scale scores on the upper-limb coordination subtest were lower than normative values, with mean difference 5.08 (95%CI; 2.35 to 7.81), p = 0.006. The mean standard score difference in high-risk patients was lower than normative on the manual coordination composite, 8.18 (95%CI; 2.26 to 14.1), p = 0.015. High-risk children also performed below the BOT-2 normative on manual dexterity 2.82 (95%CI; 0.14 to 5.78), p = 0.035 and upper limb coordination subtest 4.10 (95%CI; 1.13 to 7.05), p = 0.028. We found a decrease in fine motor precision in children with a higher BMI, rho= -0.87, p = 0.056 and a negative correlation between older age and lower manual dexterity, r= -0.41 p = 0.026; however, we did not find any correlation with the weeks in the maintenance phase. CONCLUSIONS: Fine motor impairments are common in children with ALL in the maintenance phase; it is important to identify these impairments to early rehabilitation.

Assuntos

Destreza Motora , Leucemia-Linfoma Linfoblástico de Células Precursoras , Masculino , Feminino , Humanos , Criança , Estudos Transversais , Desenvolvimento Infantil , Desempenho Psicomotor

RESUMO

The therapy of children with acute lymphoblastic leukemia (ALL) in limited resource geospaces is challenging and must balance safety, efficacy, availability, and affordability. We modified the control arm of the St. Jude Total XI protocol for outpatient delivery including once-weekly daunorubicin and vincristine in initial therapy, postponing intrathecal chemotherapy until day 22, prophylactic oral antibiotics/antimycotics, use of generic drugs, and no central nervous system (CNS) radiation. Data were interrogated from 104 consecutive children ≤12 years (median, 6 years [interquartile range (IQR), 3, 9 years]. All therapies were given in an outpatient setting in 72 children. Median follow-up is 56 months (IQR 20, 126 months). A total of 88 children achieved a hematological complete remission. Median event-free survival (EFS) is 87 months [95% confidence interval (CI), 39, 60], 7.6 years in low-risk children (3.4, 8 years) whereas 2.5 years (1, 10 years) in high-risk children. The 5-year cumulative incidence of relapse (CIR) is 28% (18, 35%), 26% (14, 37%) in low-risk children and 35% (14, 52%) in high-risk children. Median survival for all subjects is not reached but must exceed 5 years. A total of 36 children relapsed at a median of 12 months (5, 23 months). Outcomes were comparable to those reported in the control arm of the Total Therapy XI study, but inferior to current treatment protocols in high-income countries. The average cost of the first 2 years of therapy was $28,500 USD compared with an average cost of approximately $150,000 USD in the US, an 80% saving. In conclusion, using an outpatient-based modification of the St. Jude Total XI protocol, we obtained good results with relatively few hospitalizations or adverse events and at a substantial saving. This model can be applied in other resource-poor geospaces.

RESUMO

BACKGROUND: This systematic review aimed to investigate the radiological features of lymphomas and leukaemias affecting the jaws. METHODS: A systematic literature review was conducted using the electronic databases of PubMed, Web of Science and Scopus. Articles that contained sufficient radiographic examinations (periapical, panoramic or computed tomography images) for individual cases were included. Additionally, either immunohistochemical or molecular confirmation was required prior to inclusion. Three authors evaluated and described the image quality and radiological features. RESULTS: From an initial 1079 articles screened, 129 cases were included, containing 88 tomographic, 76 panoramic and 26 periapical examinations. The quality of the majority of images was sufficient for evaluation. Diffuse large B-cell lymphoma, Burkitt lymphoma, leukemic infiltration, plasmablastic lymphoma and extranodal Natural killer (NK)/T-cell lymphoma, nasal type were the most common subtypes. Involved teeth presented with mobility in 37.2% of the cases and a provisional diagnosis of inflammatory/infectious dental disease was considered in 49.2% of cases. Computed tomography exams were available for 76% of the cases, with most presented with an osteolytic lesion with ill-defined borders. Periosteal reactions were uncommon. CONCLUSION: Lymphoma/leukaemia infiltrates of the jaw bones are usually of high-grade subtypes and rarely present with periosteal reactions.

Assuntos

Leucemia , Linfoma Difuso de Grandes Células B , Humanos , Linfoma Difuso de Grandes Células B/patologia , Radiografia , Arcada Osseodentária/diagnóstico por imagem , Arcada Osseodentária/patologia

Assuntos

Leucemia Mieloide Aguda , Vimblastina , Humanos , Vimblastina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucocitose , Leucaférese

RESUMO

Feline leukaemia virus (FeLV) is a retrovirus that infects domestic and wild cats around the world. FeLV infection is associated with the development of neoplasms, bone marrow disorders and immunosuppression. Viral subgroups arise from mutations in the FeLV genome or from recombination of FeLV with ancestral endogenous retroviruses in the cat genome. The retroviral endogenisation process has allowed generation of a diversity of endogenous viruses, both functional and defective. These elements may be part of the normal functioning of the feline genome and may also interact with FeLV to form recombinant FeLV subgroups, enhance pathogenicity of viral subgroups, or inhibit and/or regulate other retroviral infections. Recombination of the env gene occurs most frequently and appears to be the most significant in terms of both the quantity and diversification of pathogenic effects in the viral population, as well as affecting cell tropism and types of disease that occur in infected cats. This review focuses on available information regarding genetic diversity, pathogenesis and diagnosis of FeLV as a result of the interaction between endogenous and exogenous viruses.

Assuntos

Doenças do Gato , Retrovirus Endógenos , Leucemia Felina , Infecções por Retroviridae , Gatos , Animais , Vírus da Leucemia Felina/genética , Vírus da Leucemia Felina/metabolismo , Retrovirus Endógenos/genética , Leucemia Felina/genética , Genes env , Infecções por Retroviridae/veterinária , Infecções por Retroviridae/genética , Doenças do Gato/genética

Assuntos

Linfoma de Burkitt , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Citometria de Fluxo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Neoplasia Residual

RESUMO

Cat ownership is common in Chile, but data on the regional prevalence of infectious agents are limited. A sero-molecular survey of 120 client- or shelter-owned domestic cats in greater Santiago was performed. Whole blood DNA was tested for the novel hepatitis-B-like virus, domestic cat hepadnavirus (DCH) by conventional PCR (cPCR) and quantitative PCR (qPCR), and for feline leukaemia virus (FeLV) by qPCR. Point-of-care serology for FeLV p27 antigen and antibodies recognising feline immunodeficiency virus (FIV) p15 and p24 was performed. DCH DNA was detected in the serum of 2/120 cats (1.67%). Sequencing and phylogenetic analysis showed that the DCH detected in Chile occupies a position outside the main clustering of DCH in the near-complete genome tree. Progressive (antigen-positive, provirus-positive) and regressive (antigen-negative, provirus-positive) FeLV infections were identified in 6/120 (5%) and 9/120 (7.5%) of cats. A total of 2/120 (1.7%) cats had dual FeLV/FIV infection, and another 2 cats had FIV infection alone. This study shows that the global footprint of DCH includes South America with a low molecular frequency in Chile, similar to that reported in the USA. Progressive FeLV infection is relatively common in urban Chile, and male cats are at greater risk than females. Testing and control measures for pathogenic retroviruses are indicated. The potential impact of FeLV, FIV and DCH on Chile's wildcat species is worthy of further investigation.

Assuntos

Hepadnaviridae , Vírus da Imunodeficiência Felina , Leucemia Felina , Humanos , Feminino , Gatos , Animais , Retroviridae , Chile/epidemiologia , Filogenia , Vírus da Leucemia Felina/genética , Vírus da Imunodeficiência Felina/genética , DNA

RESUMO

Background: The distribution of RUNX1-RUNXT1, PML-RARA, CBFB-MYH11, BCR-ABL1p210 , and KMT2A-MLLT3 in the pediatric population with acute myeloid leukemia (AML) in many countries of Latin America is largely unknown. Therefore, we aimed to investigate the frequency of these fusion genes in children with de novo AML from Mexico City, which has one of the highest incidence rates of acute leukemia in the world. Additionally, we explored their impact in mortality during the first year of treatment. Methods: We retrospectively analyzed the presence of RUNX1-RUNXT1, PML-RARA, CBFB-MYH11, BCR-ABL1p210 , and KMT2A-MLLT3 by RT-PCR among 77 patients (<18 years) diagnosed with de novo AML between 2019 and 2021 in nine Mexico City hospitals. Results: The overall frequency of the fusion genes was 50.7%; RUNX1-RUNXT1 (22.1%) and PML-RARA (20.8%) were the most prevalent, followed by CBFB-MYH11 (5.2%) and BCR-ABL1p210 (2.4%). KMT2A-MLLT3 was not detected. Patients with PML-RARA showed the lowest survival with high early mortality events. However, more studies are required to evaluate the impact of analyzed fusion genes on the overall survival of the Mexican child population with AML. Conclusion: The pediatric population of Mexico City with AML had frequencies of AML1-ETO, PML-RARA, CBFB-MYH11, and BCR-ABL1p210 similar to those of other populations around the world. Patients with BCR-ABL1p210 and CBFB-MYH11 were few or did not die, while those with MLL-AF9 was not detected. Although patients with PML-RARA had a low survival and a high early mortality rate, further studies are needed to determine the long-term impacts of these fusion genes on this Latino population.

RESUMO

We report 31 new compounds designed, synthesized and evaluated on Bcr-Abl, BTK and FLT3-ITD as part of our program to develop 2,6,9-trisubstituted purine derivatives as inhibitors of oncogenic kinases. The design was inspired by the chemical structures of well-known kinase inhibitors and our previously developed purine derivatives. The synthesis of these purines was simple and used a microwave reactor for the final step. Kinase assays showed three inhibitors with high selectivity for each protein that were identified: 4f (IC50 = 70 nM for Bcr-Abl), 5j (IC50 = 0.41 µM for BTK) and 5b (IC50 = 0.38 µM for FLT-ITD). The 3D-QSAR analysis and molecular docking studies suggested that two fragments are potent and selective inhibitors of these three kinases: a substitution at the 6-phenylamino ring and the length and volume of the alkyl group at N-9. The N-7 and the N-methyl-piperazine moiety linked to the aminophenyl ring at C-2 are also requirements for obtaining the activity. Furthermore, most of these purine derivatives were shown to have a significant inhibitory effect in vitro on the proliferation of leukaemia and lymphoma cells (HL60, MV4-11, CEM, K562 and Ramos) at low concentrations. Finally, we show that the selected purines (4i, 5b and 5j) inhibit the downstream signalling of the respective kinases in cell models. Thus, this study provides new evidence regarding how certain chemical modifications of purine ring substituents provide novel inhibitors of target kinases as potential anti-leukaemia drugs.

RESUMO

Bone marrow aging is associated with multiple cellular dysfunctions, including perturbed haematopoiesis, the propensity to haematological transformation, and the maintenance of leukaemia. It has been shown that instructive signals from different leukemic cells are delivered to stromal cells to remodel the bone marrow into a supportive leukemic niche. In particular, cellular senescence, a physiological program with both beneficial and deleterious effects on the health of the organisms, may be responsible for the increased incidence of haematological malignancies in the elderly and for the survival of diverse leukemic cells. Here, we will review the connection between BM aging and cellular senescence and the role that these processes play in leukaemia progression. Specifically, we discuss the role of mesenchymal stem cells as a central component of the supportive niche. Due to the specificity of the genetic defects present in leukaemia, one would think that bone marrow alterations would also have particular changes, making it difficult to envisage a shared therapeutic use. We have tried to summarize the coincident features present in BM stromal cells during aging and senescence and in two different leukaemias, acute myeloid leukaemia, with high frequency in the elderly, and B-acute lymphoblastic leukaemia, mainly a childhood disease. We propose that mesenchymal stem cells are similarly affected in these different leukaemias, and that the changes that we observed in terms of cellular function, redox balance, genetics and epigenetics, soluble factor repertoire and stemness are equivalent to those occurring during BM aging and cellular senescence. These coincident features may be used to explore strategies useful to treat various haematological malignancies.

RESUMO

5-Azacitidine has been used before stem cell transplantation in juvenile myelomonocytic leukaemia (JMML) patients. Recently, we have described immunophenotypic features in JMML at diagnosis. Here, our aim was to examine the changes in the immunophenotypic features during azacitidine treatment, correlating it with clinical response. Patients treated with 5-azacitidine were evaluated at diagnosis and after three and six cycles of medication. Among 32 patients entering the study, 28 patients were examined after three cycles and 25 patients after six. Patients showed a reduction in CD34/CD117+ cells: median 3.35% at diagnosis, 2.8% after three cycles and 1.63% after six. B-cell progenitors were decreased at diagnosis and decreased after treatment. Monocytes decreased: 11.91% to 6.4% and 4.18% respectively. Complete response was associated with increase in classical monocytes. T lymphocytes, reduced at diagnosis, increased in patients responding to 5-azacitidine. Immunophenotypic aberrancies including expression of CD7 in myeloid progenitors remained after treatment. This feature was associated with a worse response to treatment, as well as presence of NF1. Immunophenotyping was feasible in all patients. Clinical response was associated with a decrease of myeloid progenitors and monocytes and a rise in T lymphocytes although phenotypic aberrancies persisted. The largest effect was observed after three cycles.

Assuntos

Leucemia Mielomonocítica Juvenil , Antígenos CD34 , Azacitidina/uso terapêutico , Humanos , Imunofenotipagem , Contagem de Linfócitos

RESUMO

The osteogenic differentiation potential of mesenchymal stromal cells (hMSCs) is an essential process for the haematopoiesis and the maintenance of haematopoietic stem cells (HSCs). Therefore, the aim of this work was to evaluate this potential in hMSCs from AML patients (hMSCs-AML) and whether it is associated with BMP4 expression. The results showed that bone formation potential in vivo was reduced in hMSCs-AML compared to hMSCs from healthy donors (hMSCs-HD). Moreover, the fact that hMSCs-AML were not able to develop supportive haematopoietic cells or to differentiate into osteocytes suggests possible changes in the bone marrow microenvironment. Furthermore, the expression of BMP4 was decreased, indicating a lack of gene expression committed to the osteogenic lineage. Overall, these alterations could be associated with changes in the maintenance of HSCs, the leukaemic transformation process and the development of AML.