RESUMO
The polycomb complex component Bmi1 promotes the maintenance of stem cells in multiple postnatal tissues, partly by negatively regulating the expression of p16Ink4a and p19Arf, tumor suppressors associated with cellular senescence. However, deficiency for p16Ink4a and p19Arf only partially rescues the function of Bmi1-deficient stem cells. We conditionally deleted Bmi1 from adult hematopoietic cells and found that this slowly depleted hematopoietic stem cells (HSCs). Rather than inducing senescence, Bmi1 deficiency increased HSC division. The increased cell division was caused partly by increased Aristaless-related homeobox (ARX) transcription factor expression, which also increased ribosomal RNA expression. However, ARX deficiency did not rescue HSC depletion. Bmi1 deficiency also increased protein synthesis, protein aggregation, and protein ubiquitylation independent of its effects on cell division and p16Ink4a, p19Arf, and ARX expression. Bmi1 thus promotes HSC quiescence by negatively regulating ARX expression and promotes proteostasis by suppressing protein synthesis. This highlights a new connection between the regulation of stem cell maintenance and proteostasis.
Assuntos
Inibidor p16 de Quinase Dependente de Ciclina , Proteostase , Inibidor p16 de Quinase Dependente de Ciclina/genética , Células-Tronco Hematopoéticas , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 1/metabolismo , Agregados Proteicos , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , RNA Ribossômico/metabolismoRESUMO
PURPOSE: Prone position has recently gained renewed importance as a treatment for acute respiratory distress syndrome and spine and brain surgeries. Our study aimed to perform an error grid analysis to examine the clinical discrepancies between arterial blood pressure (ABP) and non-invasive blood pressure (NIBP) in the prone position and to investigate the risk factors influencing these differences. METHODS: Error grid analysis was performed retrospectively on 1389 pairs of 100 consecutive prone positioning cases. This analysis classifies the difference between the two methods into five clinically relevant zones, from "no risk" to "dangerous risk". Additionally, multivariable ordinal logistic regression analysis was conducted to evaluate the relationship between the risk zones of mean blood pressure (MBP), as classified by error grid analysis and the covariate of interest. RESULTS: Error grid analysis showed that the proportions of measurement pairs in risk zones A-E for systolic blood pressure were 96.8%, 3.2%, 0.1%, 0%, and 0%, respectively. In contrast, the MBP proportions were 74.0%, 25.1%, 0.9%, 0.1%, and 0%. Multivariable ordinal logistic regression analysis revealed that the position of arms (next to the head) was a significant factor (adjusted odds ratio: 4.35, 95% CI: 2.38-8.33, P < 0.001). CONCLUSION: Error grid analysis revealed a clinically unacceptable discrepancy between ABP and NIBP for MBP during prone positioning surgery. The position of the arms next to the head was associated with increased clinical discrepancy between the two MBP measurement methods.
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Self-renewal is the process by which stem cells divide to make more stem cells, perpetuating the stem cell pool throughout life. Self-renewal is division with maintenance of the undifferentiated state. This requires cell cycle control and often maintenance of multipotency or pluripotency, depending on the stem cell. Self-renewal programs involve networks that balance proto-oncogenes (promoting self-renewal), gate-keeping tumor suppressors (limiting self-renewal), and care-taking tumor suppressors (maintaining genomic integrity). These cell-intrinsic mechanisms are regulated by cell-extrinsic signals from the niche, the microenvironment that maintains stem cells and regulates their function in tissues. In response to changing tissue demands, stem cells undergo changes in cell cycle status and developmental potential over time, requiring different self-renewal programs at different stages of life. Reduced stem cell function and tissue regenerative capacity during aging are caused by changes in self-renewal programs that augment tumor suppression. Cancer arises from mutations that inappropriately activate self-renewal programs.
Assuntos
Células-Tronco/citologia , Animais , Ciclo Celular , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Transdução de SinaisRESUMO
Oncogenic mutations confer on cells the ability to propagate indefinitely, but whether oncogenes alter the cell fate of these cells is unknown. Here, we show that the transcriptional regulator PRDM16s causes oncogenic fate conversion by transforming cells fated to form platelets and erythrocytes into myeloid leukemia stem cells (LSCs). Prdm16s expression in megakaryocyte-erythroid progenitors (MEPs), which normally lack the potential to generate granulomonocytic cells, caused AML by converting MEPs into LSCs. Prdm16s blocked megakaryocytic/erythroid potential by interacting with super enhancers and activating myeloid master regulators, including PU.1. A CRISPR dropout screen confirmed that PU.1 is required for Prdm16s-induced leukemia. Ablating PU.1 attenuated leukemogenesis and reinstated the megakaryocytic/erythroid potential of leukemic MEPs in mouse models and human AML with PRDM16 rearrangement. Thus, oncogenic PRDM16 s expression gives MEPs an LSC fate by activating myeloid gene regulatory networks.
Assuntos
Transformação Celular Neoplásica/patologia , Proteínas de Ligação a DNA/genética , Leucemia Mieloide Aguda/patologia , Células Progenitoras de Megacariócitos e Eritrócitos/patologia , Fatores de Transcrição/genética , Animais , Transformação Celular Neoplásica/genética , Regulação Leucêmica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Leucemia Mieloide Aguda/genética , Células Progenitoras de Megacariócitos e Eritrócitos/metabolismo , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas/genética , Transativadores/genética , Translocação GenéticaRESUMO
Altered metabolism fuels 2 hallmark properties of cancer cells: unlimited proliferation and differentiation blockade. Adenosine monophosphate-activated protein kinase (AMPK) is a master regulator of bioenergetics crucial for glucose metabolism in acute myeloid leukemia (AML), and its inhibition delays leukemogenesis, but whether the metabolic function of AMPK alters the AML epigenome remains unknown. Here, we demonstrate that AMPK maintains the epigenome of MLL-rearranged AML by linking acetyl-coenzyme A (CoA) homeostasis to Bromodomain and Extra-Terminal domain (BET) protein recruitment to chromatin. AMPK deletion reduced acetyl-CoA and histone acetylation, displacing BET proteins from chromatin in leukemia-initiating cells. In both mouse and patient-derived xenograft AML models, treating with AMPK and BET inhibitors synergistically suppressed AML. Our results provide a therapeutic rationale to target AMPK and BET for AML therapy.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Acetilcoenzima A/metabolismo , Proteínas de Ciclo Celular/metabolismo , Leucemia Mieloide Aguda/metabolismo , Fatores de Transcrição/metabolismo , Acetilação , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Regulação Leucêmica da Expressão Gênica , Histonas/metabolismo , Homeostase , Humanos , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/patologia , Camundongos , Gradação de Tumores , Ligação Proteica , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
AMP-activated protein kinase (AMPK) regulates cellular energy homeostasis by inhibiting anabolic and activating catabolic processes. While AMPK activation has been extensively studied, mechanisms that inhibit AMPK remain elusive. Here we report that glycogen synthase kinase 3 (GSK3) inhibits AMPK function. GSK3 forms a stable complex with AMPK through interactions with the AMPK ß regulatory subunit and phosphorylates the AMPK α catalytic subunit. This phosphorylation enhances the accessibility of the activation loop of the α subunit to phosphatases, thereby inhibiting AMPK kinase activity. Surprisingly, PI3K-Akt signaling, which is a major anabolic signaling and normally inhibits GSK3 activity, promotes GSK3 phosphorylation and inhibition of AMPK, thus revealing how AMPK senses anabolic environments in addition to cellular energy levels. Consistently, disrupting GSK3 function within the AMPK complex sustains higher AMPK activity and cellular catabolic processes even under anabolic conditions, indicating that GSK3 acts as a critical sensor for anabolic signaling to regulate AMPK.
Assuntos
Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Proteínas Quinases Ativadas por AMP/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Linhagem Celular , Células HEK293 , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Subunidades Proteicas , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
Sexually dimorphic mammalian tissues, including sexual organs and the brain, contain stem cells that are directly or indirectly regulated by sex hormones. An important question is whether stem cells also exhibit sex differences in physiological function and hormonal regulation in tissues that do not show sex-specific morphological differences. The terminal differentiation and function of some haematopoietic cells are regulated by sex hormones, but haematopoietic stem-cell function is thought to be similar in both sexes. Here we show that mouse haematopoietic stem cells exhibit sex differences in cell-cycle regulation by oestrogen. Haematopoietic stem cells in female mice divide significantly more frequently than in male mice. This difference depends on the ovaries but not the testes. Administration of oestradiol, a hormone produced mainly in the ovaries, increased haematopoietic stem-cell division in males and females. Oestrogen levels increased during pregnancy, increasing haematopoietic stem-cell division, haematopoietic stem-cell frequency, cellularity, and erythropoiesis in the spleen. Haematopoietic stem cells expressed high levels of oestrogen receptor-α (ERα). Conditional deletion of ERα from haematopoietic stem cells reduced haematopoietic stem-cell division in female, but not male, mice and attenuated the increases in haematopoietic stem-cell division, haematopoietic stem-cell frequency, and erythropoiesis during pregnancy. Oestrogen/ERα signalling promotes haematopoietic stem-cell self-renewal, expanding splenic haematopoietic stem cells and erythropoiesis during pregnancy.
Assuntos
Estrogênios/metabolismo , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Animais , Contagem de Células , Divisão Celular/efeitos dos fármacos , Eritropoese , Receptor alfa de Estrogênio/metabolismo , Estrogênios/farmacologia , Feminino , Células-Tronco Hematopoéticas/efeitos dos fármacos , Masculino , Camundongos , Ovário/efeitos dos fármacos , Ovário/metabolismo , Gravidez , Caracteres Sexuais , Transdução de Sinais/efeitos dos fármacos , Baço/citologiaRESUMO
Little is known about metabolic regulation in stem cells and how this modulates tissue regeneration or tumour suppression. We studied the Lkb1 tumour suppressor and its substrate AMP-activated protein kinase (AMPK), kinases that coordinate metabolism with cell growth. Deletion of the Lkb1 (also called Stk11) gene in mice caused increased haematopoietic stem cell (HSC) division, rapid HSC depletion and pancytopenia. HSCs depended more acutely on Lkb1 for cell-cycle regulation and survival than many other haematopoietic cells. HSC depletion did not depend on mTOR activation or oxidative stress. Lkb1-deficient HSCs, but not myeloid progenitors, had reduced mitochondrial membrane potential and ATP levels. HSCs deficient for two catalytic α-subunits of AMPK (AMPK-deficient HSCs) showed similar changes in mitochondrial function but remained able to reconstitute irradiated mice. Lkb1-deficient HSCs, but not AMPK-deficient HSCs, exhibited defects in centrosomes and mitotic spindles in culture, and became aneuploid. Lkb1 is therefore required for HSC maintenance through AMPK-dependent and AMPK-independent mechanisms, revealing differences in metabolic and cell-cycle regulation between HSCs and some other haematopoietic progenitors.
Assuntos
Ciclo Celular/fisiologia , Metabolismo Energético/fisiologia , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Quinases Ativadas por AMP/química , Proteínas Quinases Ativadas por AMP/deficiência , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Aneuploidia , Animais , Domínio Catalítico/genética , Morte Celular , Divisão Celular , Sobrevivência Celular , Centrossomo/patologia , Ativação Enzimática , Feminino , Deleção de Genes , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/patologia , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Complexos Multiproteicos , Pancitopenia/genética , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/genética , Proteínas/metabolismo , Regeneração , Transdução de Sinais , Sirolimo/farmacologia , Fuso Acromático/patologia , Serina-Treonina Quinases TOR/metabolismoRESUMO
Epigenetic dysregulation is involved in the initiation and progression of many epithelial cancers. BMI1, a component of the polycomb protein family, plays a key role in these processes by controlling the histone ubiquitination and long-term repression of multiple genomic loci. BMI1 has previously been implicated in pancreatic homeostasis and the function of pancreatic cancer stem cells. However, no work has yet addressed its role in the early stages of pancreatic cancer development. Here, we show that BMI1 is required for the initiation of murine pancreatic neoplasia using a novel conditional knockout of Bmi1 in combination with a Kras(G12D)-driven pancreatic cancer mouse model. We also demonstrate that the requirement for Bmi1 in pancreatic carcinogenesis is independent of the Ink4a/Arf locus and at least partially mediated by dysregulation of reactive oxygen species. Our data provide new evidence of the importance of this epigenetic regulator in the genesis of pancreatic cancer.
Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Complexo Repressor Polycomb 1/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Animais , Transformação Celular Neoplásica/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Camundongos Knockout , Camundongos Mutantes , Camundongos Transgênicos , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Pâncreas/metabolismo , Pâncreas/patologia , Neoplasias Pancreáticas/genética , Complexo Repressor Polycomb 1/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Espécies Reativas de Oxigênio/metabolismoRESUMO
Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy primarily driven by an immature population of AML cells termed leukemia stem cells (LSCs) that are implicated in AML development, chemoresistance, and relapse. An emerging area of research in AML focuses on identifying and targeting the aberrant metabolism in LSCs. Dysregulated metabolism is involved in sustaining functional properties of LSCs, impeding myeloid differentiation, and evading programmed cell death, both in the process of leukemogenesis and in response to chemotherapy. This review discusses recent discoveries regarding the aberrant metabolic processes of AML LSCs that have begun to change the therapeutic landscape of AML.
RESUMO
Hematopoietic stem cells (HSCs) are capable of regenerating the blood system, but the instructive cues that direct HSCs to regenerate particular lineages lost to the injury remain elusive. Here, we show that iron is increasingly taken up by HSCs during anemia and induces erythroid gene expression and regeneration in a Tet2-dependent manner. Lineage tracing of HSCs reveals that HSCs respond to hemolytic anemia by increasing erythroid output. The number of HSCs in the spleen, but not bone marrow, increases upon anemia and these HSCs exhibit enhanced proliferation, erythroid differentiation, iron uptake, and TET2 protein expression. Increased iron in HSCs promotes DNA demethylation and expression of erythroid genes. Suppressing iron uptake or TET2 expression impairs erythroid genes expression and erythroid differentiation of HSCs; iron supplementation, however, augments these processes. These results establish that the physiological level of iron taken up by HSCs has an instructive role in promoting erythroid-biased differentiation of HSCs.
Assuntos
Anemia , Dioxigenases , Humanos , Baço , Células-Tronco Hematopoéticas/metabolismo , Diferenciação Celular , Ferro/metabolismo , Anemia/metabolismo , Células Eritroides , Proteínas de Ligação a DNA/metabolismo , Dioxigenases/metabolismoRESUMO
Normal hematopoietic stem and progenitor cells (HSPCs) inherently accumulate somatic mutations and lose clonal diversity with age, processes implicated in the development of myeloid malignancies 1 . The impact of exogenous stressors, such as cancer chemotherapies, on the genomic integrity and clonal dynamics of normal HSPCs is not well defined. We conducted whole-genome sequencing on 1,032 single-cell-derived HSPC colonies from 10 patients with multiple myeloma (MM), who had undergone various chemotherapy regimens. Our findings reveal that melphalan treatment distinctly increases mutational burden with a unique mutation signature, whereas other MM chemotherapies do not significantly affect the normal mutation rate of HSPCs. Among these therapy-induced mutations were several oncogenic drivers such as TET2 and PPM1D . Phylogenetic analysis showed a clonal architecture in post-treatment HSPCs characterized by extensive convergent evolution of mutations in genes such as TP53 and PPM1D . Consequently, the clonal diversity and structure of post-treatment HSPCs mirror those observed in normal elderly individuals, suggesting an accelerated clonal aging due to chemotherapy. Furthermore, analysis of matched therapy-related myeloid neoplasm (t-MN) samples, which occurred 1-8 years later, enabled us to trace the clonal origin of t-MNs to a single HSPC clone among a group of clones with competing malignant potential, indicating the critical role of secondary mutations in dictating clonal dominance and malignant transformation. Our findings suggest that cancer chemotherapy promotes an oligoclonal architecture with multiple HSPC clones possessing competing leukemic potentials, setting the stage for the selective emergence of a singular clone that evolves into t-MNs after acquiring secondary mutations. These results underscore the importance of further systematic research to elucidate the long-term hematological consequences of cancer chemotherapy.
RESUMO
Early diagnosis of acute myeloid leukemia (AML) in the pre-leukemic stage remains a clinical challenge, as pre-leukemic patients show no symptoms, lacking any known morphological or numerical abnormalities in blood cells. Here, we demonstrate that platelets with structurally abnormal mitochondria emerge at the pre-leukemic phase of AML, preceding detectable changes in blood cell counts or detection of leukemic blasts in blood. We visualized frozen-hydrated platelets from mice at different time points during AML development in situ using electron cryo-tomography (cryo-ET) and identified intracellular organelles through an unbiased semi-automatic process followed by quantitative measurement. A large proportion of platelets exhibited changes in the overall shape and depletion of organelles in AML. Notably, 23% of platelets in pre-leukemic cells exhibit abnormal, round mitochondria with unfolded cristae, accompanied by a significant drop in ATP levels and altered expression of metabolism-related gene signatures. Our study demonstrates that detectable structural changes in pre-leukemic platelets may serve as a biomarker for the early diagnosis of AML.
Assuntos
Plaquetas/citologia , Hematopoese , Leucemia Mieloide Aguda/diagnóstico , Tomografia Computadorizada por Raios X/métodos , Animais , Feminino , CamundongosRESUMO
Deregulation of transcription is a hallmark of acute myeloid leukemia (AML) that drives oncogenic expression programs and presents opportunities for therapeutic targeting. By integrating comprehensive pan-cancer enhancer landscapes with genetic dependency mapping, we find that AML-enriched enhancers encode for more selective tumor dependencies. We hypothesized that this approach could identify actionable dependencies downstream of oncogenic driver events and discovered a MYB-regulated AML-enriched enhancer regulating SEPHS2, a key component of the selenoprotein production pathway. Using a combination of patient samples and mouse models, we show that this enhancer upregulates SEPHS2, promoting selenoprotein production and antioxidant function required for AML survival. SEPHS2 and other selenoprotein pathway genes are required for AML growth in vitro. SEPHS2 knockout and selenium dietary restriction significantly delay leukemogenesis in vivo with little effect on normal hematopoiesis. These data validate the utility of enhancer mapping in target identification and suggest that selenoprotein production is an actionable target in AML.
Assuntos
Leucemia Mieloide Aguda , Selênio , Animais , Carcinogênese/genética , Elementos Facilitadores Genéticos/genética , Humanos , Leucemia Mieloide Aguda/patologia , Camundongos , Oncogenes , Selênio/uso terapêuticoRESUMO
Metabolic dysregulation underlies malignant phenotypes attributed to cancer stem cells, such as unlimited proliferation and differentiation blockade. Here, we demonstrate that NAD+ metabolism enables acute myeloid leukemia (AML) to evade apoptosis, another hallmark of cancer stem cells. We integrated whole-genome CRISPR screening and pan-cancer genetic dependency mapping to identify NAMPT and NMNAT1 as AML dependencies governing NAD+ biosynthesis. While both NAMPT and NMNAT1 were required for AML, the presence of NAD+ precursors bypassed the dependence of AML on NAMPT but not NMNAT1, pointing to NMNAT1 as a gatekeeper of NAD+ biosynthesis. Deletion of NMNAT1 reduced nuclear NAD+, activated p53, and increased venetoclax sensitivity. Conversely, increased NAD+ biosynthesis promoted venetoclax resistance. Unlike leukemia stem cells (LSCs) in both murine and human AML xenograft models, NMNAT1 was dispensable for hematopoietic stem cells and hematopoiesis. Our findings identify NMNAT1 as a previously unidentified therapeutic target that maintains NAD+ for AML progression and chemoresistance.
Assuntos
Leucemia Mieloide Aguda , Nicotinamida-Nucleotídeo Adenililtransferase , Animais , Apoptose/genética , Homeostase , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Camundongos , NAD/metabolismo , Células-Tronco Neoplásicas/metabolismo , Nicotinamida-Nucleotídeo Adenililtransferase/genética , Nicotinamida-Nucleotídeo Adenililtransferase/metabolismoRESUMO
Hematopoiesis serves as a paradigm for how homeostasis is maintained within hierarchically organized cell populations. However, important questions remain as to the contribution of hematopoietic stem cells (HSCs) toward maintaining steady state hematopoiesis. A number of in vivo lineage labeling and propagation studies have given rise to contradictory interpretations, leaving key properties of stem cell function unresolved. Using processed flow cytometry data coupled with a biology-driven modeling approach, we show that in vivo flux experiments that come from different laboratories can all be reconciled into a single unifying model, even though they had previously been interpreted as being contradictory. We infer from comparative analysis that different transgenic models display distinct labeling efficiencies across a heterogeneous HSC pool, which we validate by marker gene expression associated with HSC function. Finally, we show how the unified model of HSC differentiation can be used to simulate clonal expansion in the early stages of leukemogenesis.
Assuntos
Células-Tronco Hematopoéticas/metabolismo , Leucemia/patologia , Modelos Biológicos , Animais , Biomarcadores/metabolismo , Carcinogênese/patologia , Autorrenovação Celular , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Integrases/metabolismo , Cinética , Camundongos Transgênicos , Receptor TIE-2/metabolismo , Coloração e RotulagemRESUMO
Histone variants contribute to the complexity of the chromatin landscape and play an integral role in defining DNA domains and regulating gene expression. The histone H3 variant H3.3 is incorporated into genic elements independent of DNA replication by its chaperone HIRA. Here we demonstrate that Hira is required for the self-renewal of adult hematopoietic stem cells (HSCs) and to restrain erythroid differentiation. Deletion of Hira led to rapid depletion of HSCs while differentiated hematopoietic cells remained largely unaffected. Depletion of HSCs after Hira deletion was accompanied by increased expression of bivalent and erythroid genes, which was exacerbated upon cell division and paralleled increased erythroid differentiation. Assessing H3.3 occupancy identified a subset of polycomb-repressed chromatin in HSCs that depends on HIRA to maintain the inaccessible, H3.3-occupied state for gene repression. HIRA-dependent H3.3 incorporation thus defines distinct repressive chromatin that represses erythroid differentiation of HSCs.
Assuntos
Células-Tronco Adultas/metabolismo , Proteínas de Ciclo Celular/genética , Diferenciação Celular/genética , Células Eritroides/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Chaperonas de Histonas/genética , Fatores de Transcrição/genética , Fatores Etários , Animais , Animais Recém-Nascidos , Proteínas de Ciclo Celular/metabolismo , Autorrenovação Celular/genética , Perfilação da Expressão Gênica/métodos , Ontologia Genética , Hematopoese/genética , Chaperonas de Histonas/metabolismo , Histonas/genética , Histonas/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , RNA-Seq/métodos , Fatores de Transcrição/metabolismoRESUMO
Clonal hematopoiesis (CH) has emerged as an important factor linked to adverse health conditions in the elderly. CH is characterized by an overrepresentation of genetically distinct hematopoietic stem cell clones in the peripheral blood. Whereas the genetic mutations that underlie CH have been closely scrutinized, relatively little attention has been paid to the environmental factors that may influence the emergence of one dominant stem cell clone. As there is huge individual variation in latency between acquisition of a genetic mutation and emergence of CH, environmental factors likely play a major role. Indeed, environmental stressors such as inflammation, chemotherapy, and metabolic syndromes are known to affect steady-state hematopoiesis. To date, epidemiologic studies point toward smoking and prior chemotherapy exposure as likely contributors to some forms of CH, though the impact of other environmental factors is also being investigated. Mechanistic studies in murine models indicate that the role of different environmental factors in CH emergence may be highly specific to the mutation that marks each stem cell clone. For instance, recent studies have found that clones with mutations in the PPM1D gene are more resistant to genotoxic stress induced by chemotherapy. These clones thus have a competitive advantage in the setting of chemotherapy, but not in other types of stress. Here we review currently available literature on the interplay between environment and the genetic landscapes in CH and highlight critical areas for future study. Improved understanding of the effects of environmental stress on emergence of CH with mutation-specific clarity will guide future efforts to provide preventive medicine to individuals with CH.
Assuntos
Evolução Clonal , Exposição Ambiental/efeitos adversos , Doenças Hematológicas , Hematopoese/genética , Células-Tronco Hematopoéticas/metabolismo , Mutação , Animais , Dano ao DNA , Modelos Animais de Doenças , Doenças Hematológicas/genética , Doenças Hematológicas/metabolismo , Doenças Hematológicas/patologia , Células-Tronco Hematopoéticas/patologia , Humanos , Camundongos , Proteína Fosfatase 2C/genética , Proteína Fosfatase 2C/metabolismoRESUMO
Energy stress depletes ATP and induces cell death. Here we identify an unexpected inhibitory role of energy stress on ferroptosis, a form of regulated cell death induced by iron-dependent lipid peroxidation. We found that ferroptotic cell death and lipid peroxidation can be inhibited by treatments that induce or mimic energy stress. Inactivation of AMP-activated protein kinase (AMPK), a sensor of cellular energy status, largely abolishes the protective effects of energy stress on ferroptosis in vitro and on ferroptosis-associated renal ischaemia-reperfusion injury in vivo. Cancer cells with high basal AMPK activation are resistant to ferroptosis and AMPK inactivation sensitizes these cells to ferroptosis. Functional and lipidomic analyses further link AMPK regulation of ferroptosis to AMPK-mediated phosphorylation of acetyl-CoA carboxylase and polyunsaturated fatty acid biosynthesis. Our study demonstrates that energy stress inhibits ferroptosis partly through AMPK and reveals an unexpected coupling between ferroptosis and AMPK-mediated energy-stress signalling.