RESUMO
ABSTRACT: Epidemiological studies report opposing influences of infection on childhood B-cell acute lymphoblastic leukemia (B-ALL). Although infections in the first year of life appear to exert the largest impact on leukemia risk, the effect of early pathogen exposure on the fetal preleukemia cells (PLC) that lead to B-ALL has yet to be reported. Using cytomegalovirus (CMV) infection as a model early-life infection, we show that virus exposure within 1 week of birth induces profound depletion of transplanted E2A-PBX1 and hyperdiploid B-ALL cells in wild-type recipients and in situ-generated PLC in Eµ-ret mice. The age-dependent depletion of PLC results from an elevated STAT4-mediated cytokine response in neonates, with high levels of interleukin (IL)-12p40-driven interferon (IFN)-γ production inducing PLC death. Similar PLC depletion can be achieved in adult mice by impairing viral clearance. These findings provide mechanistic support for potential inhibitory effects of early-life infection on B-ALL progression and could inform novel therapeutic or preventive strategies.
Assuntos
Modelos Animais de Doenças , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Animais , Camundongos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Infecções por Citomegalovirus , Pré-Leucemia/genética , Pré-Leucemia/patologia , Camundongos Endogâmicos C57BL , Animais Recém-Nascidos , DiploideRESUMO
ABSTRACT: The spectrum of myeloid disorders ranges from aplastic bone marrow failure characterized by an empty bone marrow completely lacking in hematopoiesis to acute myeloid leukemia in which the marrow space is replaced by undifferentiated leukemic blasts. Recent advances in the capacity to sequence bulk tumor population as well as at a single-cell level has provided significant insight into the stepwise process of transformation to acute myeloid leukemia. Using models of progression in the context of germ line predisposition (trisomy 21, GATA2 deficiency, and SAMD9/9L syndrome), premalignant states (clonal hematopoiesis and clonal cytopenia of unknown significance), and myelodysplastic syndrome, we review the mechanisms of progression focusing on the hierarchy of clonal mutation and potential roles of transcription factor alterations, splicing factor mutations, and the bone marrow environment in progression to acute myeloid leukemia. Despite major advances in our understanding, preventing the progression of these disorders or treating them at the acute leukemia phase remains a major area of unmet medical need.
Assuntos
Progressão da Doença , Humanos , Pré-Leucemia/patologia , Pré-Leucemia/genética , Síndromes Mielodisplásicas/patologia , Síndromes Mielodisplásicas/genética , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/genética , Animais , Lesões Pré-Cancerosas/patologia , Lesões Pré-Cancerosas/genética , Mutação , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Transformação Celular Neoplásica/metabolismoRESUMO
T(8;21)(q22;q22), which generates the AML1-ETO fusion oncoprotein, is a common chromosomal abnormality in acute myeloid leukemia (AML) patients. Despite having favorable prognosis, 40% of patients will relapse, highlighting the need for innovative models and application of the newest technologies to study t(8;21) leukemogenesis. Currently, available AML1-ETO mouse models have limited utility for studying the pre-leukemic stage because AML1-ETO produces mild hematopoietic phenotypes and no leukemic transformation. Conversely, overexpression of a truncated variant, AML1-ETO9a (AE9a), promotes fully penetrant leukemia and is too potent for studying pre-leukemic changes. To overcome these limitations, we devised a germline-transmitted Rosa26 locus AE9a knock-in mouse model that moderately overexpressed AE9a and developed leukemia with long latency and low penetrance. We observed pre-leukemic alterations in AE9a mice, including skewing of progenitors towards granulocyte/monocyte lineages and replating of stem and progenitor cells. Next, we performed single-cell RNA sequencing to identify specific cell populations that contribute to these pre-leukemic phenotypes. We discovered a subset of common myeloid progenitors that have heightened granulocyte/monocyte bias in AE9a mice. We also observed dysregulation of key hematopoietic transcription factor target gene networks, blocking cellular differentiation. Finally, we identified Sox4 activation as a potential contributor to stem cell self-renewal during the pre-leukemic stage.
Assuntos
Leucemia Mieloide Aguda , Pré-Leucemia , Humanos , Camundongos , Animais , Proteína 1 Parceira de Translocação de RUNX1/genética , Leucemia Mieloide Aguda/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Animais Geneticamente Modificados , Análise de Sequência de RNA , Proteínas de Fusão Oncogênica/genéticaRESUMO
Acute myeloid leukemia (AML) arises from preleukemic conditions. We have investigated the pathogenesis of typical preleukemia, myeloproliferative neoplasms, and clonal hematopoiesis. Hematopoietic stem cells in both preleukemic conditions harbor recurrent driver mutations; additional mutation provokes further malignant transformation, leading to AML onset. Although genetic alterations are defined as the main cause of malignant transformation, non-genetic factors are also involved in disease progression. In this review, we focus on a non-histone chromatin protein, high mobility group AT-hook2 (HMGA2), and a physiological p53 inhibitor, murine double minute X (MDMX). HMGA2 is mainly overexpressed by dysregulation of microRNAs or mutations in polycomb components, and provokes expansion of preleukemic clones through stem cell signature disruption. MDMX is overexpressed by altered splicing balance in myeloid malignancies. MDMX induces leukemic transformation from preleukemia via suppression of p53 and p53-independent activation of WNT/ß-catenin signaling. We also discuss how these non-genetic factors can be targeted for leukemia prevention therapy.
Assuntos
Leucemia Mieloide Aguda , Pré-Leucemia , Animais , Camundongos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Mutação , Pré-Leucemia/genética , Pré-Leucemia/patologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
Transcriptional variability facilitates stochastic cell diversification and can in turn underpin adaptation to stress or injury. We hypothesize that it may analogously facilitate progression of premalignancy to cancer. To investigate this, we initiated preleukemia in mouse cells with enhanced transcriptional variability due to conditional disruption of the histone lysine acetyltransferase gene Kat2a. By combining single-cell RNA sequencing of preleukemia with functional analysis of transformation, we show that Kat2a loss results in global variegation of cell identity and accumulation of preleukemic cells. Leukemia progression is subsequently facilitated by destabilization of ribosome biogenesis and protein synthesis, which confer a transient transformation advantage. The contribution of transcriptional variability to early cancer evolution reflects a generic role in promoting cell fate transitions, which, in the case of well-adapted malignancies, contrastingly differentiates and depletes cancer stem cells. That is, transcriptional variability confers forward momentum to cell fate systems, with differential multistage impact throughout cancer evolution.
Assuntos
Leucemia , Pré-Leucemia , Animais , Diferenciação Celular , Leucemia/genética , Camundongos , Pré-Leucemia/genética , Pré-Leucemia/patologia , Biossíntese de ProteínasRESUMO
Leukemia is the most usual childhood cancer, and B-cell acute lymphoblastic leukemia (B-ALL) is its most common presentation. It has been proposed that pediatric leukemogenesis occurs through a "multi-step" or "multi-hit" mechanism that includes both in utero and postnatal steps. Many childhood leukemia-initiating events, such as chromosomal translocations, originate in utero, and studies so far suggest that these "first-hits" occur at a far higher frequency than the incidence of childhood leukemia itself. The reason why only a small percentage of the children born with such preleukemic "hits" will develop full-blown leukemia is still a mystery. In order to better understand childhood leukemia, mouse modeling is essential, but only if the multistage process of leukemia can be recapitulated in the model. Therefore, mouse models naturally reproducing the "multi-step" process of childhood B-ALL will be essential to identify environmental or other factors that are directly linked to increased risk of disease.
Assuntos
Síndromes Mielodisplásicas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Pré-Leucemia , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Pré-Leucemia/genética , Translocação GenéticaRESUMO
Preleukemic has been used to describe children with a propensity to develop B cell acute lymphoblastic leukemia (B-ALL). However, leukemia-predisposing mutations can also be present in differentiated cells unable to transform. We postulate that preleukemia should only be used when such mutations arise in progenitors capable of evolving to B-ALL.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Pré-Leucemia , Criança , Humanos , Pré-Leucemia/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , MutaçãoRESUMO
The conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) is a key step in DNA demethylation that is mediated by ten-eleven translocation (TET) enzymes, which require ascorbate/vitamin C. Here, we report the 5hmC landscape of normal hematopoiesis and identify cell type-specific 5hmC profiles associated with active transcription and chromatin accessibility of key hematopoietic regulators. We utilized CRISPR/Cas9 to model TET2 loss-of-function mutations in primary human hematopoietic stem and progenitor cells (HSPC). Disrupted cells exhibited increased colonies in serial replating, defective erythroid/megakaryocytic differentiation, and in vivo competitive advantage and myeloid skewing coupled with reduction of 5hmC at erythroid-associated gene loci. Azacitidine and ascorbate restored 5hmC abundance and slowed or reverted the expansion of TET2-mutant clones in vivo. These results demonstrate the key role of 5hmC in normal hematopoiesis and TET2-mutant phenotypes and raise the possibility of utilizing these agents to further our understanding of preleukemia and clonal hematopoiesis. SIGNIFICANCE: We show that 5-hydroxymethylation profiles are cell type-specific and associated with transcriptional abundance and chromatin accessibility across human hematopoiesis. TET2 loss caused aberrant growth and differentiation phenotypes and disrupted 5hmC and transcriptional landscapes. Treatment of TET2 KO HSPCs with ascorbate or azacitidine reverted 5hmC profiles and restored aberrant phenotypes. This article is highlighted in the In This Issue feature, p. 265.
Assuntos
Dioxigenases , Síndromes Mielodisplásicas , Pré-Leucemia , Azacitidina/farmacologia , Cromatina/genética , Proteínas de Ligação a DNA/genética , Dioxigenases/genética , Hematopoese/genética , Humanos , Proteínas Proto-Oncogênicas/genéticaRESUMO
Children with Down syndrome have a 150-fold increased risk of developing myeloid leukemia, but the mechanism of predisposition is unclear. Because Down syndrome leukemogenesis initiates during fetal development, we characterized the cellular and developmental context of preleukemic initiation and leukemic progression using gene editing in human disomic and trisomic fetal hematopoietic cells and xenotransplantation. GATA binding protein 1 (GATA1) mutations caused transient preleukemia when introduced into trisomy 21 long-term hematopoietic stem cells, where a subset of chromosome 21 microRNAs affected predisposition to preleukemia. By contrast, progression to leukemia was independent of trisomy 21 and originated in various stem and progenitor cells through additional mutations in cohesin genes. CD117+/KIT proto-oncogene (KIT) cells mediated the propagation of preleukemia and leukemia, and KIT inhibition targeted preleukemic stem cells.
Assuntos
Proteínas de Ciclo Celular/genética , Síndrome de Down/genética , Fator de Transcrição GATA1/genética , Células-Tronco Hematopoéticas/fisiologia , Leucemia Mieloide/genética , Pré-Leucemia/genética , Animais , Antígenos CD34/análise , Proteínas de Ciclo Celular/metabolismo , Linhagem da Célula , Proliferação de Células , Transformação Celular Neoplásica , Proteínas Cromossômicas não Histona/genética , Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 21/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Síndrome de Down/complicações , Feminino , Fator de Transcrição GATA1/metabolismo , Hematopoese , Transplante de Células-Tronco Hematopoéticas , Xenoenxertos , Humanos , Leucemia Mieloide/metabolismo , Leucemia Mieloide/patologia , Fígado/embriologia , Masculino , Megacariócitos/fisiologia , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Mutação , Pré-Leucemia/metabolismo , Pré-Leucemia/patologia , Inibidores de Proteínas Quinases/farmacologia , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-kit/análise , Proteínas Proto-Oncogênicas c-kit/antagonistas & inibidores , CoesinasRESUMO
t(4;11) MLL-AF4 acute leukemia is one of the most aggressive malignancies in the infant and pediatric population, yet we have little information on the molecular mechanisms responsible for disease progression. This impairs the development of therapeutic regimens that can address the aggressive phenotype and lineage plasticity of MLL-AF4-driven leukemogenesis. This study highlights novel mechanisms of disease development by focusing on 2 microRNAs (miRNAs) upregulated in leukemic blasts from primary patient samples: miR-130b and miR-128a. We show that miR-130b and miR-128a are downstream targets of MLL-AF4 and can individually drive the transition from a pre-leukemic stage to an acute leukemia in an entirely murine Mll-AF4 in vivo model. They are also required to maintain the disease phenotype. Interestingly, miR-130b overexpression led to a mixed/B-cell precursor (BCP)/myeloid leukemia, propagated by the lymphoid-primed multipotent progenitor (LMPP) population, whereas miR-128a overexpression resulted in a pro-B acute lymphoblastic leukemia (ALL), maintained by a highly expanded Il7r+c-Kit+ blast population. Molecular and phenotypic changes induced by these two miRNAs fully recapitulate the human disease, including central nervous system infiltration and activation of an MLL-AF4 expression signature. Furthermore, we identified 2 downstream targets of these miRNAs, NR2F6 and SGMS1, which in extensive validation studies are confirmed as novel tumor suppressors of MLL-AF4+ leukemia. Our integrative approach thus provides a platform for the identification of essential co-drivers of MLL-rearranged leukemias, in which the preleukemia to leukemia transition and lineage plasticity can be dissected and new therapeutic approaches can be tested.
Assuntos
Leucemia Mieloide Aguda/genética , MicroRNAs/genética , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Animais , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Feminino , Regulação Leucêmica da Expressão Gênica , Humanos , Masculino , Camundongos , Pré-Leucemia/genética , Fatores de Elongação da Transcrição/genética , Translocação GenéticaRESUMO
B cell acute lymphoblastic leukaemia (B-ALL) is the most common form of childhood cancer. Although treatment has advanced remarkably in the past 50 years, it still fails in ~20% of patients. Recent studies revealed that more than 5% of healthy newborns carry preleukaemic clones that originate in utero, but only a small percentage of these carriers will progress to overt B-ALL. The drivers of progression are unclear, but B-ALL incidence seems to be increasing in parallel with the adoption of modern lifestyles. Emerging evidence shows that a major driver for the conversion from the preleukaemic state to the B-ALL state is exposure to immune stressors, such as infection. Here, we discuss our current understanding of the environmental triggers and genetic predispositions that may lead to B-ALL, highlighting lessons from epidemiology, the clinic and animal models, and identifying priority areas for future research.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras B/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Animais , Carcinogênese/genética , Criança , Interação Gene-Ambiente , Predisposição Genética para Doença , Humanos , Infecções/complicações , Microbiota/imunologia , Modelos Biológicos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Células Precursoras de Linfócitos B/imunologia , Células Precursoras de Linfócitos B/metabolismo , Pré-Leucemia/etiologia , Pré-Leucemia/genética , Pré-Leucemia/imunologia , Fatores de Risco , Microambiente Tumoral/genética , Microambiente Tumoral/imunologiaAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Hematopoiese Clonal , Leucemia Mieloide Aguda/induzido quimicamente , Síndromes Mielodisplásicas/induzido quimicamente , Segunda Neoplasia Primária/induzido quimicamente , Neuroblastoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Evolução Clonal , Terapia Combinada , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Mutação , Agonistas Mieloablativos/efeitos adversos , Agonistas Mieloablativos/uso terapêutico , Segunda Neoplasia Primária/genética , Segunda Neoplasia Primária/fisiopatologia , Neuroblastoma/tratamento farmacológico , Pré-Leucemia/induzido quimicamente , Pré-Leucemia/genética , Pré-Leucemia/fisiopatologia , Condicionamento Pré-Transplante/efeitos adversos , Transplante AutólogoRESUMO
Haematopoietic stem and progenitor cells (HSPCs) are defined as unspecialized cells that give rise to more differentiated cells. In a similar way, leukaemic stem and progenitor cells (LSPCs) are defined as unspecialized leukaemic cells, which can give rise to more differentiated cells. Leukaemic cells carry leukaemic mutations/variants and have clear differentiation abnormalities. Pre-leukaemic HSPCs (PreL-HSPCs) carry pre-leukaemic mutations/variants (pLMs) and are capable of producing mature functional cells, which will carry the same variants. Under the roof of LSPCs, one can find a broad range of cell types genetic and disease phenotypes. Present-day knowledge suggests that this phenotypic heterogeneity is the result of interactions between the cell of origin, the genetic background and the microenvironment background. The combination of these attributes will define the LSPC phenotype, frequency, differentiation capacity and evolutionary trajectory. Importantly, as LSPCs are leukaemia-initiating cells that sustain clinical remission and are the source of relapse, an improved understanding of LSPCs phenotype would offer better clinical opportunities for the treatment and hopefully prevention of human leukaemia. The current review will focus on LSPCs attributes in the context of human haematologic malignancies.
Assuntos
Células-Tronco Hematopoéticas/patologia , Leucemia/patologia , Pré-Leucemia/patologia , Biomarcadores Tumorais , Medula Óssea/patologia , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Variação Genética , Hematopoese , Humanos , Leucemia/genética , Leucemia/metabolismo , Mutação , Fenótipo , Pré-Leucemia/genética , Pré-Leucemia/metabolismo , Microambiente TumoralRESUMO
Precise replacement of diseased or dysfunctional organs is the goal of regenerative medicine and has appeared to be a distant goal for a long time. In the field of hematopoietic stem cell transplantation, this goal is now becoming tangible as gene-editing technologies and novel conditioning agents are entering the clinical arena. Targeted immunologic depletion of hematopoietic stem cells (HSCs), which are at the very root of the hematopoietic system, will enable more selective and potentially more effective hematopoietic stem cell transplantation in patients with hematological diseases. In contrast to current conditioning regimes based on ionizing radiation and chemotherapy, immunologic conditioning will spare mature hematopoietic cells and cause substantially less inflammation and unspecific collateral damage to other organs. Biological agents that target the stem cell antigen CD117 are the frontrunners for this purpose and have exhibited preclinical activity in depletion of healthy HSCs. The value of anti-CD117 antibodies as conditioning agents is currently being evaluated in early clinical trials. Whereas mild, antibody-based immunologic conditioning concepts might be appropriate for benign hematological disorders in which incomplete replacement of diseased cells is sufficient, higher efficacy will be required for treatment and elimination of hematologic stem cell malignancies such as acute myeloid leukemia and myelodysplastic syndrome. Antibody-drug conjugates, bispecific T-cell engaging and activating antibodies (TEAs), or chimeric antigen receptor (CAR) T cells might offer increased efficacy compared with naked antibodies and yet higher tolerability and safety compared with current genotoxic conditioning approaches. Here, we summarize the current state regarding immunologic conditioning concepts for the treatment of HSC disorders and outline potential future developments.
Assuntos
Antineoplásicos/farmacologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Imunoterapia/métodos , Células-Tronco Neoplásicas/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-kit/antagonistas & inibidores , Condicionamento Pré-Transplante/métodos , Animais , Anticorpos Biespecíficos/uso terapêutico , Protocolos de Ensaio Clínico como Assunto , Hematopoiese Clonal , Terapia Combinada , Doenças Genéticas Inatas/terapia , Neoplasias Hematológicas/terapia , Hematopoese , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunoglobulina G/imunologia , Imunoglobulina G/uso terapêutico , Imunoterapia Adotiva , Imunotoxinas/uso terapêutico , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicas/terapia , Pré-Leucemia/terapia , Proteínas Proto-Oncogênicas c-kit/biossíntese , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/imunologia , Medição de Risco , Imunodeficiência Combinada Severa/terapiaAssuntos
Biomarcadores Tumorais/genética , Bases de Dados Factuais , Leucemia Mieloide Aguda/patologia , Mutação , Síndromes Mielodisplásicas/patologia , Pré-Leucemia/patologia , Adulto , Feminino , Seguimentos , Humanos , Leucemia Mieloide Aguda/genética , Masculino , Síndromes Mielodisplásicas/genética , Pré-Leucemia/genética , Prognóstico , Fatores SexuaisRESUMO
Isocitrate dehydrogenase (IDH) mutations are common genetic alterations in myeloid disorders, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Epigenetic changes, including abnormal histone and DNA methylation, have been implicated in the pathogenic build-up of hematopoietic progenitors, but it is still unclear whether and how IDH mutations themselves affect hematopoiesis. Here, we show that IDH1-mutant mice develop myeloid dysplasia in that these animals exhibit anemia, ineffective erythropoiesis, and increased immature progenitors and erythroblasts. In erythroid cells of these mice, D-2-hydroxyglutarate, an aberrant metabolite produced by the mutant IDH1 enzyme, inhibits oxoglutarate dehydrogenase activity and diminishes succinyl-coenzyme A (CoA) production. This succinyl-CoA deficiency attenuates heme biosynthesis in IDH1-mutant hematopoietic cells, thus blocking erythroid differentiation at the late erythroblast stage and the erythroid commitment of hematopoietic stem cells, while the exogenous succinyl-CoA or 5-ALA rescues erythropoiesis in IDH1-mutant erythroid cells. Heme deficiency also impairs heme oxygenase-1 expression, which reduces levels of important heme catabolites such as biliverdin and bilirubin. These deficits result in accumulation of excessive reactive oxygen species that induce the cell death of IDH1-mutant erythroid cells. Our results clearly show the essential role of IDH1 in normal erythropoiesis and describe how its mutation leads to myeloid disorders. These data thus have important implications for the devising of new treatments for IDH-mutant tumors.
Assuntos
Eritropoese/genética , Células-Tronco Hematopoéticas/metabolismo , Heme/biossíntese , Isocitrato Desidrogenase/genética , Mutação de Sentido Incorreto , Mutação Puntual , Pré-Leucemia/genética , Acil Coenzima A/biossíntese , Acil Coenzima A/deficiência , Anemia/genética , Animais , Medula Óssea/patologia , Eritroblastos/metabolismo , Técnicas de Introdução de Genes , Glutaratos/metabolismo , Heme/deficiência , Heme Oxigenase-1/metabolismo , Isocitrato Desidrogenase/fisiologia , Complexo Cetoglutarato Desidrogenase/antagonistas & inibidores , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Células Mieloides/patologia , Mielopoese/genética , Pré-Leucemia/metabolismo , Pré-Leucemia/patologia , Espécies Reativas de Oxigênio/metabolismo , Proteínas Recombinantes/metabolismo , Esplenomegalia/etiologia , Trombocitopenia/genéticaAssuntos
Alelos , Proteínas Estimuladoras de Ligação a CCAAT/genética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Mutação , Pré-Leucemia/diagnóstico , Pré-Leucemia/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Linhagem da Célula , Humanos , PrognósticoRESUMO
In normal dividing tissues, cell homeostasis is maintained by rare cellular elements, the stem cells, that have the unique property of self-renewal and differentiation to generate a population of functionally mature tissue elements. Recent studies carried out in the last three decades support the existence of stem cells also in tumors, the so-called cancer stem cells. Cancer stem cells have the property of initiating and maintaining tumor growth, are able to self-renew and to differentiate, are the main drivers of intra- and inter-tumoral heterogeneity and the main cellular mediators of drug resistance, leading to tumor recurrence and metastasis. Cancer stem cells can be identified in many tumors according to specific immunophenotypic features, but cancer stemness cannot be defined as a fixed property, due to cancer plasticity. For these properties, cancer stem cells represent attractive targets for developing new anti-cancer therapies and there is supporting evidence that the combination of conventional anticancer therapies with drugs targeting cancer stem cells could lead to cancer eradication. Ongoing studies in some tumors strongly support the clinical utility of developing efficient strategies of cancer stem cell targeting.
Assuntos
Terapia de Alvo Molecular , Células-Tronco Neoplásicas/efeitos dos fármacos , Carcinogênese , Testes de Carcinogenicidade , Ensaios Clínicos como Assunto , Células Clonais/patologia , Humanos , Leucemia/tratamento farmacológico , Leucemia/patologia , Metástase Neoplásica , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Pré-Leucemia/tratamento farmacológico , Pré-Leucemia/patologia , Transdução de Sinais/efeitos dos fármacosRESUMO
Patients with the pre-leukemia bone marrow failure syndrome called severe congenital neutropenia (CN) have an approximately 15% risk of developing acute myeloid leukemia (AML; called here CN/AML). Most CN/AML patients co-acquire CSF3R and RUNX1 mutations, which play cooperative roles in the development of AML. To establish an in vitro model of leukemogenesis, we utilized bone marrow lin- cells from transgenic C57BL/6-d715 Csf3r mice expressing a CN patient-mimicking truncated CSF3R mutation. We transduced these cells with vectors encoding RUNX1 wild type (WT) or RUNX1 mutant proteins carrying the R139G or R174L mutations. Cells transduced with these RUNX1 mutants showed diminished in vitro myeloid differentiation and elevated replating capacity, compared with those expressing WT RUNX1. mRNA expression analysis showed that cells transduced with the RUNX1 mutants exhibited hyperactivation of inflammatory signaling and innate immunity pathways, including IL-6, TLR, NF-kappaB, IFN, and TREM1 signaling. These data suggest that the expression of mutated RUNX1 in a CSF3R-mutated background may activate the pro-inflammatory cell state and inhibit myeloid differentiation.
Assuntos
Síndrome Congênita de Insuficiência da Medula Óssea/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Células-Tronco Hematopoéticas/patologia , Células Mieloides/patologia , Mielopoese/genética , Neutropenia/congênito , Pré-Leucemia/genética , Receptores de Fator Estimulador de Colônias/genética , Animais , Divisão Celular , Ensaio de Unidades Formadoras de Colônias , Síndrome Congênita de Insuficiência da Medula Óssea/patologia , Subunidade alfa 2 de Fator de Ligação ao Core/fisiologia , Perfilação da Expressão Gênica , Imunidade Inata , Inflamação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neutropenia/genética , Neutropenia/patologia , Pré-Leucemia/patologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Receptores de Fator Estimulador de Colônias/fisiologia , Proteínas Recombinantes/genética , Organismos Livres de Patógenos EspecíficosRESUMO
There is clear evidence that ionizing radiation (IR) causes leukemia. For many types of leukemia, the preleukemic fusion genes (PFG), as consequences of DNA damage and chromosomal translocations, occur in hematopoietic stem and progenitor cells (HSPC) in utero and could be detected in umbilical cord blood (UCB) of newborns. However, relatively limited information is available about radiation-induced apoptosis, DNA damage and PFG formation in human HSPC. In this study we revealed that CD34+ HSPC compared to lymphocytes: (i) are extremely radio-resistant showing delayed time kinetics of apoptosis, (ii) accumulate lower level of endogenous DNA damage/early apoptotic γH2AX pan-stained cells, (iii) have higher level of radiation-induced 53BP1 and γH2AX/53BP1 co-localized DNA double stranded breaks, and (iv) after low dose of IR may form very low level of BCR-ABL PFG. Within CD34+ HSPC we identified CD34+CD38+ progenitor cells as a highly apoptosis-resistant population, while CD34+CD38- hematopoietic stem/multipotent progenitor cells (HSC/MPP) as a population very sensitive to radiation-induced apoptosis. Our study provides critical insights into how human HSPC respond to IR in the context of DNA damage, apoptosis and PFG.