RESUMEN
AIMS: Acute Myeloid Leukemia (AML) is an invasive and lethal blood cancer caused by a rare population of Leukemia Stem Cells (LSCs). Telomerase activation is a limitless self-renewal process in LSCs. Apart from telomerase role in telomere lengthening, telomerase (especially hTERT subunit) inhibits intrinsic-, extrinsic-, and p53- mediated apoptosis pathways. In this study, the effect of Telomerase Inhibition (TI) on intrinsic-, extrinsic-, p53-mediated apoptosis, and DNMT3a and TET epigenetic markers in stem (CD34+) and differentiated (CD34-) AML cells is evaluated. MAIN METHODS: High-purity CD34+ (primary AML and KG-1a) cells were enriched using the Magnetic-Activated Cell Sorting (MACS) system. CD34+ and CD34- (primary AML and KG-1a) cells were treated with BIBR1532 and then, MTT assay, Annexin V/7AAD, Ki-67 assay, Telomere Length (TL) measurement, and transcriptional alterations of p53, hTERT, TET2, DNMT3a were analyzed. Finally, apoptosis-related genes and proteins were studied. KEY FINDINGS: TI with the IC50 values of 83.5, 33.2, 54.3, and 24.6 µM in CD34+ and CD34- (primary AML and KG-1a) cells significantly inhibited cell proliferation and induced apoptosis. However, TI had no significant effect on TL. The results also suggested TI induced intrinsic-, extrinsic-, and p53-mediated apoptosis. It was shown that the expression levels of DNMT3a and TET2 epigenetic markers were highly increased following TI. SIGNIFICANCE: In total, it was revealed that TI induced apoptosis through intrinsic, extrinsic, and p53 pathways and increased the expression of DNMT3a and TET2 epigenetic markers.
Asunto(s)
Leucemia Mieloide Aguda/fisiopatología , Células Madre Neoplásicas/metabolismo , Telomerasa/metabolismo , Anciano , Aminobenzoatos/farmacología , Antígenos CD34/metabolismo , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , ADN Metiltransferasa 3A/metabolismo , Inhibidores Enzimáticos/farmacología , Femenino , Humanos , Leucemia Mieloide Aguda/metabolismo , Masculino , Persona de Mediana Edad , Naftalenos/farmacología , Cultivo Primario de Células , Telomerasa/antagonistas & inhibidores , Telomerasa/fisiologíaRESUMEN
Acute myeloid leukemia (AML) cells rely on phospho-signaling pathways to gain unlimited proliferation potential. Here, we use domain-focused CRISPR screening and identify the nuclear phosphatase SCP4 as a dependency in AML, yet this enzyme is dispensable in normal hematopoietic progenitor cells. Using CRISPR exon scanning and gene complementation assays, we show that the catalytic function of SCP4 is essential in AML. Through mass spectrometry analysis of affinity-purified complexes, we identify the kinase paralogs STK35 and PDIK1L as binding partners and substrates of the SCP4 phosphatase domain. We show that STK35 and PDIK1L function catalytically and redundantly in the same pathway as SCP4 to maintain AML proliferation and to support amino acid biosynthesis and transport. We provide evidence that SCP4 regulates STK35/PDIK1L through two distinct mechanisms: catalytic removal of inhibitory phosphorylation and by promoting kinase stability. Our findings reveal a phosphatase-kinase signaling complex that supports the pathogenesis of AML.
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Leucemia Mieloide Aguda/metabolismo , Fosfoproteínas Fosfatasas/metabolismo , Transducción de Señal/fisiología , Línea Celular Tumoral , Proliferación Celular/genética , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/fisiopatología , Fosfoproteínas Fosfatasas/fisiología , Fosforilación , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/fisiologíaRESUMEN
A common feature of both congenital and acquired forms of bone marrow failure is an increased risk of developing acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Indeed, the development of MDS or AML is now the major cause of mortality in patients with congenital neutropenia. Thus, there is a pressing clinical need to develop better strategies to prevent, diagnose early, and treat MDS/AML in patients with congenital neutropenia and other bone marrow failure syndromes. Here, we discuss recent data characterizing clonal hematopoiesis and progression to myeloid malignancy in congenital neutropenia, focusing on severe congenital neutropenia (SCN) and Shwachman-Diamond syndrome. We summarize recent studies showing excellent outcomes after allogenic hematopoietic stem cell transplantation for many (but not all) patients with congenital neutropenia, including patients with SCN with active myeloid malignancy who underwent transplantation. Finally, we discuss how these new data inform the current clinical management of patients with congenital neutropenia.
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Síndromes Congénitos de Insuficiencia de la Médula Ósea/complicaciones , Leucemia Mieloide Aguda/etiología , Síndromes Mielodisplásicos/etiología , Mielopoyesis , Neutropenia/congénito , Preescolar , Hematopoyesis Clonal , Síndromes Congénitos de Insuficiencia de la Médula Ósea/fisiopatología , Síndromes Congénitos de Insuficiencia de la Médula Ósea/terapia , Trasplante de Células Madre Hematopoyéticas , Humanos , Lactante , Leucemia Mieloide Aguda/fisiopatología , Leucemia Mieloide Aguda/terapia , Persona de Mediana Edad , Síndromes Mielodisplásicos/fisiopatología , Síndromes Mielodisplásicos/terapia , Neutropenia/complicaciones , Neutropenia/fisiopatología , Neutropenia/terapia , Síndrome de Shwachman-Diamond/complicaciones , Síndrome de Shwachman-Diamond/fisiopatología , Síndrome de Shwachman-Diamond/terapiaRESUMEN
Even though genetic perturbations and mutations are important for the development of myeloid malignancies, the effects of an inflammatory microenvironment are a critical modulator of carcinogenesis. Activation of the innate immune system through various ligands and signaling pathways is an important driver of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). The DAMPs, or alarmins, which activate the inflammasome pathway via the TLR4/NLR signaling cascade causes the lytic cell death of hematopoietic stem and progenitor cells (HSPCs), ineffective hematopoiesis, and ß-catenin-induced proliferation of cancer cells, leading to the development of MDS/AML phenotype. It is also associated with other myeloid malignancies and involved in the pathogenesis of associated cytopenias. Ongoing research suggests the interplay of inflammasome mediators with immune modulators and transcription factors to have a significant role in the development of myeloid diseases, and possibly therapy resistance. This review discusses the role and importance of inflammasomes and immune pathways in myeloid malignancies, particularly MDS/AML, to better understand the disease pathophysiology and decipher the scope of therapeutic interventions.
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Antineoplásicos/farmacología , Inflamasomas/antagonistas & inhibidores , Leucemia Mieloide Aguda/tratamiento farmacológico , Síndromes Mielodisplásicos/tratamiento farmacológico , Animales , Antineoplásicos/uso terapéutico , Descubrimiento de Drogas , Humanos , Inmunidad Innata/efectos de los fármacos , Inflamasomas/inmunología , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/fisiopatología , Terapia Molecular Dirigida , Síndromes Mielodisplásicos/inmunología , Síndromes Mielodisplásicos/fisiopatología , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Proteína con Dominio Pirina 3 de la Familia NLR/inmunologíaAsunto(s)
Hematopoyesis Clonal , Marcadores Genéticos , Leucemia Mieloide Aguda/fisiopatología , Mutación , Síndromes Mielodisplásicos/fisiopatología , Trastornos Mieloproliferativos/fisiopatología , Trombosis/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Trombosis/genética , Trombosis/patologíaRESUMEN
Currently there is great interest in targeting mitochondrial oxidative phosphorylation (OXPHOS) in cancer. However, notwithstanding the targeting of mutant dehydrogenases, nearly all hopeful 'mito-therapeutics' cannot discriminate cancerous from non-cancerous OXPHOS and thus suffer from a limited therapeutic index. Using acute myeloid leukemia (AML) as a model, herein, we leveraged an in-house diagnostic biochemical workflow to identify 'actionable' bioenergetic vulnerabilities intrinsic to cancerous mitochondria. Consistent with prior reports, AML growth and proliferation was associated with a hyper-metabolic phenotype which included increases in basal and maximal respiration. However, despite having nearly 2-fold more mitochondria per cell, clonally expanding hematopoietic stem cells, leukemic blasts, as well as chemoresistant AML were all consistently hallmarked by intrinsic OXPHOS limitations. Remarkably, by performing experiments across a physiological span of ATP free energy, we provide direct evidence that leukemic mitochondria are particularly poised to consume ATP. Relevant to AML biology, acute restoration of oxidative ATP synthesis proved highly cytotoxic to leukemic blasts, suggesting that active OXPHOS repression supports aggressive disease dissemination in AML. Together, these findings argue against ATP being the primary output of leukemic mitochondria and provide proof-of-principle that restoring, rather than disrupting, OXPHOS may represent an untapped therapeutic avenue for combatting hematological malignancy and chemoresistance.
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Metabolismo Energético/fisiología , Leucemia Mieloide Aguda , Fosforilación Oxidativa , Adenosina Trifosfato/metabolismo , Adolescente , Adulto , Anciano , Femenino , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/fisiopatología , Masculino , Persona de Mediana Edad , Mitocondrias/metabolismo , Mitocondrias/fisiología , Adulto JovenRESUMEN
Acute myeloid leukemia (AML) accounts for 16% of all leukemias in children. Prognosis in the pediatric population is better than that of older populations, with a younger age at diagnosis being a favorable prognostic factor [1]. Diplopia is a rare first presenting sign of AML. We present a 15 year old male complaining of diplopia and unilateral orbital swelling. Workup in the emergency department found normal neuroimaging but revealed a markedly elevated leukocytosis with anemia and thrombocytopenia. Peripheral smear showed increased blast cells >10%. This patient was ultimately diagnosed with AML. This case demonstrates an atypical presentation of AML and urges a thorough work up for patients presenting with unexplained diplopia.
Asunto(s)
Diplopía/diagnóstico , Leucemia Mieloide Aguda/complicaciones , Adolescente , Diplopía/etiología , Humanos , Leucemia Mieloide Aguda/fisiopatología , Masculino , PronósticoRESUMEN
INTRODUCTION: Acute leukemia (AL) occurring in pregnancy is extremely rare, and its treatment is a clinical dilemma. METHODS: We retrospectively reviewed the medical records of our hospital from 2010 to 2019. RESULTS: Twenty-one patients were diagnosed with AL during pregnancy. Of whom, eighteen had acute myeloid leukemia, and 3 had acute lymphoblastic leukemia. Six, eight and seven patients were diagnosed during the first, second, and third trimester, respectively. Six of the 21 patients experienced therapeutic abortion and 1 had spontaneous abortion, whereas 9 gave birth to healthy babies (4 through vaginal deliveries and 5 with Caesarean sections). Four babies had been exposed to chemotherapeutic agents, but no congenital malformations were observed. Sixteen patients received chemotherapy, while 4 patients died before chemotherapy and one was discharged after refusing chemotherapy. The complete remission rate of the 10 patients who began chemotherapy immediately after diagnosis was 80%, compared with 66.7% in the 6 patients who started chemotherapy after abortion or delivery. Three remain alive. CONCLUSIONS: In general, initiation of chemotherapy as early as possible may increase the CR rate. Combined with literature data, we proposed that, for patients diagnosed in early and late stages of pregnancy (>30 weeks), elective termination or induced delivery before chemotherapy may be a good choice for better maternal (and fetal) outcome.KEY MESSAGESAcute leukaemia diagnosed in pregnancy is extremely rare, and its treatment is a clinical dilemma.In general, initiation of chemotherapy as early as possible may increase the CR rate.For patients who are diagnosed in the first trimester or late stage of pregnancy (>30 weeks), elective termination or induced delivery before starting chemotherapy may be a good choice for better maternal (and fetal) outcome.
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Leucemia Mieloide Aguda/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Complicaciones Neoplásicas del Embarazo/terapia , Aborto Inducido , Adulto , Antineoplásicos/uso terapéutico , Femenino , Humanos , Leucemia Mieloide Aguda/fisiopatología , Leucemia-Linfoma Linfoblástico de Células Precursoras/fisiopatología , Embarazo , Complicaciones Neoplásicas del Embarazo/fisiopatología , Resultado del Embarazo , Inducción de Remisión , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
INTRODUCTION: Myeloid neoplasms with platelet-derived growth factor receptor ß (PDGFRB) rearrangement usually present with eosinophilia in the peripheral blood and bone marrow. Here we report a case of systemic mastocytosis related myeloid neoplasms with basophilia and PRKG2-PDGFRB fusion gene. PATIENTS CONCERNS: A 53-year-old male patient felt fatigue with thrombocythemia and normal hemoglobin over 2âyears. Considering the possibility of primary thrombocytosis, the patient was treated with hydroxyurea and interferon. Then the therapy was stopped due to adverse events and worsen condition. DIAGNOSIS: Acute myelogenous leukemia (AML) diagnosis was confirmed by bone marrow morphology and flow cytometry. PDGFRB rearrangement was detected by fluorescence in situ hybridization (FISH) test, with chromosome karyotype 46,XY,t(4:5)(q21:q33). PRKG2-PDGFRB fusion was observed by next generation sequencing (NGS) and verified by RT-PCR followed by Sanger sequencing. The results of bone marrow aspiration, bone marrow biopsy, and immunophenotyping showed systemic mastocytosis-related myeloid tumor with basophilia. INTERVENTIONS: Imatinib 400âmg/d was given on the day of admission. Azacitidine 75âmg/m2 was given for induction therapy for 10âdays, and followed by one course of DHAG consolidating therapy. Imatinib was taken orally continuously. OUTCOMES: On the 8th day of treatment, the patient's diet and fatigue improved. The hematological and bone marrow morphological remission was achieved on the 25th day. Cytogenetic complete remission was achieved 3âmonths later and continued to present (December 20, 2020). PRKG2-PDGFRB fusion gene turned negative 7âmonths later from diagnosis. LESSONS: Patients with increased basophilic granulocyte and/or mast cells in peripheral blood and/or bone marrow should be screened for PDGFRB abnormality and myeloid or lymphatic tumor. Patients bearing PDGFRB abnormality have a good response to imatinib.
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Basófilos/metabolismo , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/fisiopatología , Mastocitosis Sistémica/complicaciones , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Masculino , Persona de Mediana EdadRESUMEN
Inflammation-dependent base deaminases promote therapeutic resistance in many malignancies. However, their roles in human pre-leukemia stem cell (pre-LSC) evolution to acute myeloid leukemia stem cells (LSCs) had not been elucidated. Comparative whole-genome and whole-transcriptome sequencing analyses of FACS-purified pre-LSCs from myeloproliferative neoplasm (MPN) patients reveal APOBEC3C upregulation, an increased C-to-T mutational burden, and hematopoietic stem and progenitor cell (HSPC) proliferation during progression, which can be recapitulated by lentiviral APOBEC3C overexpression. In pre-LSCs, inflammatory splice isoform overexpression coincides with APOBEC3C upregulation and ADAR1p150-induced A-to-I RNA hyper-editing. Pre-LSC evolution to LSCs is marked by STAT3 editing, STAT3ß isoform switching, elevated phospho-STAT3, and increased ADAR1p150 expression, which can be prevented by JAK2/STAT3 inhibition with ruxolitinib or fedratinib or lentiviral ADAR1 shRNA knockdown. Conversely, lentiviral ADAR1p150 expression enhances pre-LSC replating and STAT3 splice isoform switching. Thus, pre-LSC evolution to LSCs is fueled by primate-specific APOBEC3C-induced pre-LSC proliferation and ADAR1-mediated splicing deregulation.
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Inflamación/inmunología , Leucemia Mieloide Aguda/fisiopatología , Proliferación Celular , Humanos , Células Madre Neoplásicas/metabolismoRESUMEN
BACKGROUND: Epigenetic therapy, using hypomethylating agents (HMA), is known to be effective in the treatment of high-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) patients who are not suitable for intensive chemotherapy and/or allogeneic stem cell transplantation. However, response rates to HMA are low and there is an unmet need in finding prognostic and predictive biomarkers of treatment response and overall survival. We performed global methylation analysis of 75 patients with high-risk MDS and secondary AML who were included in CETLAM SMD-09 protocol, in which patients received HMA or intensive treatment according to age, comorbidities and cytogenetic. RESULTS: Unsupervised analysis of global methylation pattern at diagnosis did not allow patients to be differentiated according to the cytological subtype, cytogenetic groups, treatment response or patient outcome. However, after a supervised analysis we found a methylation signature defined by 200 probes, which allowed differentiating between patients responding and non-responding to azacitidine (AZA) treatment and a different methylation pattern also defined by 200 probes that allowed to differentiate patients according to their survival. On studying follow-up samples, we confirmed that AZA decreases global DNA methylation, but in our cohort the degree of methylation decrease did not correlate with the type of response. The methylation signature detected at diagnosis was not useful in treated samples to distinguish patients who were going to relapse or progress. CONCLUSIONS: Our findings suggest that in a subset of specific CpGs, altered DNA methylation patterns at diagnosis may be useful as a biomarker for predicting AZA response and survival.
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Antimetabolitos Antineoplásicos/uso terapéutico , Azacitidina/uso terapéutico , Metilación de ADN , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/genética , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Leucemia Mieloide Aguda/fisiopatología , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/fisiopatología , Medición de Riesgo/métodos , EspañaRESUMEN
Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with poor prognosis and overall survival. Clinical investigations show that chronic stress is commonly present in the course of AML and associated with adverse outcome. However, the underlying molecular mechanisms are elusive. In the present study, a chronic restraint stress mouse model was established to evaluate the effect of stress on AML. We found that mice under chronic stress exhibited significantly increased liver and spleen infiltration of leukemic cells and poorer overall survival. This was accompanied by elevated cellular NLR family pyrin domain containing 3 (NLRP3) and interleukin-1ß (IL-1ß) in the liver or bone marrow, and secreted IL-1ß in the plasma, indicating the activation of inflammasomes under chronic restraint stress. High mobility group box 1 (HMGB1) expression was markedly increased in newly diagnosed AML patients, but reduced in complete remission AML patients. The expression level of HMGB1 was positively correlated with NLRP3 mRNA in AML patients. Knockdown of HMGB1 significantly decreased NLRP3 and IL-1ß expression in AML cell lines, and secreted IL-1ß in supernatant of AML cell culture, while HMGB1 stimulation caused contrary effects. These results implied that HMGB1 could be involved in the regulation of inflammasome activation in AML development. Mice model showed that chronic restraint stress-facilitated proliferation and infiltration of AML cells were largely abrogated by knocking down HMGB1. Knockdown of HMGB1 also ameliorated overall survival and remarkably neutralized NLRP3 and IL-1ß expression under chronic restraint stress. These findings provide evidences that chronic stress promotes AML progression via HMGB1/NLRP3/IL-1ß dependent mechanism, suggesting that HMGB1 is a potential therapeutic target for AML. KEY MESSAGES: ⢠Chronic restraint stress promoted acute myeloid leukemia (AML) progression and mediated NLRP3 inflammasome activation in xenograft mice. ⢠HMGB1 mediated NLRP3 inflammasome activation in AML cells. ⢠Knockdown of HMGB1 inhibited AML progression under chronic stress in vivo.
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Regulación Leucémica de la Expresión Génica , Proteína HMGB1/fisiología , Interleucina-1beta/fisiología , Leucemia Mieloide Aguda/fisiopatología , Proteína con Dominio Pirina 3 de la Familia NLR/fisiología , Proteínas de Neoplasias/fisiología , Transducción de Señal/fisiología , Animales , Médula Ósea/metabolismo , Línea Celular Tumoral , Enfermedad Crónica , Progresión de la Enfermedad , Femenino , Técnicas de Silenciamiento del Gen , Proteína HMGB1/antagonistas & inhibidores , Proteína HMGB1/biosíntesis , Proteína HMGB1/genética , Xenoinjertos , Humanos , Inflamasomas/metabolismo , Inflamación , Interleucina-1beta/biosíntesis , Interleucina-1beta/genética , Leucemia Mieloide Aguda/metabolismo , Hígado/metabolismo , Hígado/patología , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR/biosíntesis , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Interferencia de ARN , Inducción de Remisión , Restricción Física , Bazo/metabolismo , Bazo/patología , Estrés Fisiológico , Receptor Toll-Like 4/fisiologíaAsunto(s)
Antineoplásicos/efectos adversos , Compuestos Bicíclicos Heterocíclicos con Puentes/efectos adversos , Leucemia Mieloide Aguda/tratamiento farmacológico , Sulfonamidas/efectos adversos , Síndrome de Lisis Tumoral/etiología , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Azacitidina/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Citarabina/uso terapéutico , Decitabina/uso terapéutico , Femenino , Humanos , Leucemia Mieloide Aguda/fisiopatología , Masculino , Persona de Mediana Edad , Factores de Riesgo , Sulfonamidas/administración & dosificaciónRESUMEN
Up to 18% of patients with acute myeloid leukemia (AML) present with a white blood cell (WBC) count of greater than 100,000/µL, a condition that is frequently referred to as hyperleukocytosis. Hyperleukocytosis has been associated with an adverse prognosis and a higher incidence of life-threatening complications such as leukostasis, disseminated intravascular coagulation (DIC), and tumor lysis syndrome (TLS). The molecular processes underlying hyperleukocytosis have not been fully elucidated yet. However, the interactions between leukemic blasts and endothelial cells leading to leukostasis and DIC as well as the processes in the bone marrow microenvironment leading to the massive entry of leukemic blasts into the peripheral blood are becoming increasingly understood. Leukemic blasts interact with endothelial cells via cell adhesion molecules such as various members of the selectin family which are upregulated via inflammatory cytokines released by leukemic blasts. Besides their role in the development of leukostasis, cell adhesion molecules have also been implicated in leukemic stem cell survival and chemotherapy resistance and can be therapeutically targeted with specific inhibitors such as plerixafor or GMI-1271 (uproleselan). However, in the absence of approved targeted therapies supportive treatment with the uric acid lowering agents allopurinol and rasburicase as well as aggressive intravenous fluid hydration for the treatment and prophylaxis of TLS, transfusion of blood products for the management of DIC, and cytoreduction with intensive chemotherapy, leukapheresis, or hydroxyurea remain the mainstay of therapy for AML patients with hyperleukocytosis.
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Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/fisiopatología , Leucostasis/complicaciones , Animales , Médula Ósea/patología , Médula Ósea/fisiopatología , Comunicación Celular , Transformación Celular Neoplásica/patología , Humanos , Leucemia Mieloide Aguda/terapia , Terapia Molecular DirigidaRESUMEN
We investigated clinical associations of ficolins and mannose-binding lectin (MBL) in 157 patients suffering from acute myeloid leukaemia (AML). Concentrations of ficolin-1, ficolin-2, ficolin-3 and MBL (before chemotherapy) in serum were determined as were selected polymorphisms of the corresponding genes (FCN1, FCN2, FCN3 and MBL2). The control group (C) consisted of 267 healthy unrelated individuals. Median level of ficolin-1 in patients was lower (p < 0.000001) while median levels of ficolin-2, ficolin-3 and MBL were higher (p < 0.000001, p < 0.000001 and p = 0.0016, respectively) compared with controls. These findings were generally associated with AML itself, however the highest MBL levels predicted higher risk of severe hospital infections (accompanied with bacteremia and/or fungaemia) (p = 0.012) while the lowest ficolin-1 concentrations tended to be associated with prolonged (> 7 days) fever (p = 0.026). Genotyping indicated an association of G/G homozygosity (corresponding to FCN1 gene - 542 G > A polymorphism) with malignancy [p = 0.004, OR = 2.95, 95% CI (1.41-6.16)]. Based on ROC analysis, ficolin-1, -2 and -3 may be considered candidate supplementary biomarkers of AML. Their high potential to differentiate between patients from non-malignant controls but also from persons suffering from other haematological cancers (multiple myeloma and lymphoma) was demonstrated.
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Lectinas/genética , Leucemia Mieloide Aguda/metabolismo , Lectina de Unión a Manosa/genética , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Biomarcadores de Tumor/sangre , Lectina de Unión a Manosa de la Vía del Complemento/genética , Femenino , Frecuencia de los Genes/genética , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Lectinas/análisis , Lectinas/sangre , Leucemia Mieloide Aguda/fisiopatología , Masculino , Lectina de Unión a Manosa/análisis , Lectina de Unión a Manosa/sangre , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa/genética , Persona de Mediana Edad , Polimorfismo Genético/genética , FicolinasRESUMEN
BACKGROUND: The impact of extramedullary infiltration (EMI) on the clinical outcomes of pediatric patients with acute myeloid leukemia (AML) are controversial. PATIENTS AND METHODS: A total of 214 pediatric patients with low-risk AML were classified as having EMI (central nervous leukemia [CNSL] and/or myeloid sarcoma [MS]) and not having EMI. Patients with isolated MS before AML diagnosis by bone marrow examination were confirmed with histopathologic examination. For patients diagnosed with AML by bone marrow examination, a thorough physical examination and radiologic imaging were used to confirm MS. RESULTS: Male gender, a high white blood cell count, the FAB-M5 subtype, t(8;21) and t(1;11) abnormalities, and c-KIT mutations were associated with EMI. The presence of MS was associated with a low complete remission rate (63.6% vs. 79.4%; P = .000) and poor 3-year relapse-free survival (RFS) (62.6% ± 7.5% vs. 87.0% ± 2.8%; P = .000) and 3-year overall survival (73.5% ± 7% vs. 88.8% ± 2.6%; P = .011). Multivariate analysis revealed that MS was a poor prognostic factor for RFS and overall survival. Bone infiltration was an independent risk factor for inferior RFS with MS. Patients with CNSL had a low complete remission rate (58.3% vs. 77.2%; P = .045); however, CNSL did not significantly affect the survival of low-risk patients with AML. CONCLUSION: MS should be considered an independent risk factor to guide stratified treatment.
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Leucemia Mieloide Aguda/complicaciones , Infiltración Leucémica/fisiopatología , Niño , Femenino , Humanos , Leucemia Mieloide Aguda/fisiopatología , Masculino , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Factores de TiempoRESUMEN
The caudal-related homeobox transcription factor CDX2 is expressed in leukemic cells but not during normal blood formation. Retroviral overexpression of Cdx2 induces AML in mice, however the developmental stage at which CDX2 exerts its effect is unknown. We developed a conditionally inducible Cdx2 mouse model to determine the effects of in vivo, inducible Cdx2 expression in hematopoietic stem and progenitor cells (HSPCs). Cdx2-transgenic mice develop myelodysplastic syndrome with progression to acute leukemia associated with acquisition of additional driver mutations. Cdx2-expressing HSPCs demonstrate enrichment of hematopoietic-specific enhancers associated with pro-differentiation transcription factors. Furthermore, treatment of Cdx2 AML with azacitidine decreases leukemic burden. Extended scheduling of low-dose azacitidine shows greater efficacy in comparison to intermittent higher-dose azacitidine, linked to more specific epigenetic modulation. Conditional Cdx2 expression in HSPCs is an inducible model of de novo leukemic transformation and can be used to optimize treatment in high-risk AML.
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Factor de Transcripción CDX2/metabolismo , Células Madre Hematopoyéticas/metabolismo , Leucemia Mieloide Aguda/metabolismo , Síndromes Mielodisplásicos/metabolismo , Animales , Factor de Transcripción CDX2/genética , Transformación Celular Neoplásica , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/fisiopatología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/fisiopatologíaRESUMEN
The purpose of this study, a secondary analysis of a publicly available database, was to identify racial and ethnic disparities in the risk of severe sepsis facing children undergoing the intensive therapy necessary to treat acute myeloid leukemia (AML). The sample consisted of 1,913 hospitalizations of children, younger than 21 years, in the United States during the year 2016 with documentation of both AML and at least one infectious complication. Binary logistic regression models were used to examine the association between race/ethnicity and severe sepsis in children with AML and infection. We found that, after controlling for potential confounding variables, the odds of developing severe sepsis were significantly increased for Hispanic children compared with White children. There were no significant differences in the likelihood of the development of sepsis in Black, Asian, or other race children. The increased risk of severe sepsis for Hispanic children may contribute to the disparate rates of overall survival in this group. This inequitable rate of severe sepsis was evident despite the generally accepted practice of retaining children in the hospital throughout recovery of blood counts following AML therapy. Nurses are in a position to identify and eliminate modifiable risk factors contributing to this disparity.
Asunto(s)
Disparidades en Atención de Salud/estadística & datos numéricos , Hispánicos o Latinos/estadística & datos numéricos , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/fisiopatología , Sepsis/etiología , Sepsis/fisiopatología , Adolescente , Adulto , Negro o Afroamericano/estadística & datos numéricos , Niño , Preescolar , Femenino , Disparidades en Atención de Salud/etnología , Humanos , Leucemia Mieloide Aguda/etnología , Modelos Logísticos , Masculino , Factores de Riesgo , Sepsis/etnología , Estados Unidos/etnología , Población Blanca/estadística & datos numéricos , Adulto JovenRESUMEN
Haematopoiesis is governed by haematopoietic stem cells (HSCs) that produce all lineages of blood and immune cells. The maintenance of blood homeostasis requires a dynamic response of HSCs to stress, and dysregulation of these adaptive-response mechanisms underlies the development of myeloid leukaemia. Leukaemogenesis often occurs in a stepwise manner, with genetic and epigenetic changes accumulating in pre-leukaemic HSCs prior to the emergence of leukaemic stem cells (LSCs) and the development of acute myeloid leukaemia. Clinical data have revealed the existence of age-related clonal haematopoiesis, or the asymptomatic clonal expansion of mutated blood cells in the elderly, and this phenomenon is connected to susceptibility to leukaemic transformation. Here we describe how selection for specific mutations that increase HSC competitive fitness, in conjunction with additional endogenous and environmental changes, drives leukaemic transformation. We review the ways in which LSCs take advantage of normal HSC properties to promote survival and expansion, thus underlying disease recurrence and resistance to conventional therapies, and we detail our current understanding of leukaemic 'stemness' regulation. Overall, we link the cellular and molecular mechanisms regulating HSC behaviour with the functional dysregulation of these mechanisms in myeloid leukaemia and discuss opportunities for targeting LSC-specific mechanisms for the prevention or cure of malignant diseases.
Asunto(s)
Carcinogénesis/genética , Hematopoyesis/fisiología , Células Madre Hematopoyéticas/fisiología , Leucemia Mieloide Aguda/fisiopatología , Antineoplásicos/farmacología , Carcinogénesis/efectos de los fármacos , Carcinogénesis/patología , Interacción Gen-Ambiente , Inestabilidad Genómica/efectos de los fármacos , Inestabilidad Genómica/fisiología , Hematopoyesis/genética , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/patología , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Mutación/efectos de los fármacos , Mutación/genética , Mutación/fisiología , Nicho de Células Madre/efectos de los fármacos , Nicho de Células Madre/fisiología , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/fisiologíaRESUMEN
Leukaemogenic mutations commonly disrupt cellular differentiation and/or enhance proliferation, thus perturbing the regulatory programs that control self-renewal and differentiation of stem and progenitor cells. Translocations involving the Mll1 (Kmt2a) gene generate powerful oncogenic fusion proteins, predominantly affecting infant and paediatric AML and ALL patients. The early stages of leukaemogenic transformation are typically inaccessible from human patients and conventional mouse models. Here, we take advantage of cells conditionally blocked at the multipotent haematopoietic progenitor stage to develop a MLL-r model capturing early cellular and molecular consequences of MLL-ENL expression based on a clear clonal relationship between parental and leukaemic cells. Through a combination of scRNA-seq, ATAC-seq and genome-scale CRISPR-Cas9 screening, we identify pathways and genes likely to drive the early phases of leukaemogenesis. Finally, we demonstrate the broad utility of using matched parental and transformed cells for small molecule inhibitor studies by validating both previously known and other potential therapeutic targets.