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Leukemia stem cells (LSCs) are widely believed to reside in well-characterized bone marrow (BM) niches; however, the capacity of the BM niches to accommodate LSCs is insufficient, and a significant proportion of LSCs are instead maintained in regions outside the BM. The molecular basis for this niche-independent behavior of LSCs remains elusive. Here, we show that integrin-α9 overexpression (ITGA9 OE) plays a pivotal role in the extramedullary maintenance of LSCs by molecularly mimicking the niche-interacting status, through the binding with its soluble ligand, osteopontin (OPN). Retroviral insertional mutagenesis conducted on leukemia-prone Runx-deficient mice identified Itga9 OE as a novel leukemogenic event. Itga9 OE activates Akt and p38MAPK signaling pathways. The elevated Myc expression subsequently enhances ribosomal biogenesis to overcome the cell integrity defect caused by the preexisting Runx alteration. The Itga9-Myc axis, originally discovered in mice, was further confirmed in multiple human acute myeloid leukemia (AML) subtypes, other than RUNX leukemias. In addition, ITGA9 was shown to be a functional LSC marker of the best prognostic value among 14 known LSC markers tested. Notably, the binding of ITGA9 with soluble OPN, a known negative regulator against HSC activation, induced LSC dormancy, while the disruption of ITGA9-soluble OPN interaction caused rapid cell propagation. These findings suggest that the ITGA9 OE increases both actively proliferating leukemia cells and dormant LSCs in a well-balanced manner, thereby maintaining LSCs. The ITGA9 OE would serve as a novel therapeutic target in AML.
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The genetic lesions that drive acute megakaryoblastic leukemia (AMKL) have not been fully elucidated. To search for genetic alterations in AMKL, we performed targeted deep sequencing in 34 AMKL patient samples and 8 AMKL cell lines and detected frequent genetic mutations in the NOTCH pathway in addition to previously reported alterations in GATA-1 and the JAK-STAT pathway. Pharmacological and genetic NOTCH activation, but not inhibition, significantly suppressed AMKL cell proliferation in both in vitro and in vivo assays employing a patient-derived xenograft model. These results suggest that NOTCH inactivation underlies AMKL leukemogenesis. and NOTCH activation holds the potential for therapeutic application in AMKL.
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The molecular mechanisms governing the response of hematopoietic stem cells (HSCs) to stress insults remain poorly defined. Here, we investigated effects of conditional knock-out or overexpression of Hmga2 (High mobility group AT-hook 2), a transcriptional activator of stem cell genes in fetal HSCs. While Hmga2 overexpression did not affect adult hematopoiesis under homeostasis, it accelerated HSC expansion in response to injection with 5-fluorouracil (5-FU) or in vitro treatment with TNF-α. In contrast, HSC and megakaryocyte progenitor cell numbers were decreased in Hmga2 KO animals. Transcription of inflammatory genes was repressed in Hmga2-overexpressing mice injected with 5-FU, and Hmga2 bound to distinct regions and chromatin accessibility was decreased in HSCs upon stress. Mechanistically, we found that casein kinase 2 (CK2) phosphorylates the Hmga2 acidic domain, promoting its access and binding to chromatin, transcription of anti-inflammatory target genes, and the expansion of HSCs under stress conditions. Notably, the identified stress-regulated Hmga2 gene signature is activated in hematopoietic stem progenitor cells of human myelodysplastic syndrome patients. In sum, these results reveal a TNF-α/CK2/phospho-Hmga2 axis controlling adult stress hematopoiesis.
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Quinasa de la Caseína II , Cromatina , Proteína HMGA2 , Células Madre Hematopoyéticas , Ratones Noqueados , Proteína HMGA2/metabolismo , Proteína HMGA2/genética , Animales , Células Madre Hematopoyéticas/metabolismo , Ratones , Humanos , Quinasa de la Caseína II/metabolismo , Quinasa de la Caseína II/genética , Cromatina/metabolismo , Cromatina/genética , Factor de Necrosis Tumoral alfa/metabolismo , Hematopoyesis , Estrés Fisiológico , Fluorouracilo/farmacología , Regeneración , Fosforilación , Síndromes Mielodisplásicos/patología , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/metabolismo , Ratones Endogámicos C57BLRESUMEN
Runt-related transcription factor (RUNX) family members play critical roles in the development of multiple organs. Mammalian RUNX family members, consisting of RUNX1, RUNX2, and RUNX3, have distinct tissue-specific expression and function. In this study, we examined the spatiotemporal expression patterns of RUNX family members in developing kidneys and analyzed the role of RUNX1 during kidney development. In the developing mouse kidney, RUNX1 protein was strongly expressed in the ureteric bud (UB) tip and weakly expressed in the distal segment of the renal vesicle (RV), comma-shaped body (CSB), and S-shaped body (SSB). In contrast, RUNX2 protein was restricted to the stroma, and RUNX3 protein was only expressed in immune cells. We also analyzed the expression of RUNX family members in the cynomolgus monkey kidney. We found that expression patterns of RUNX2 and RUNX3 were conserved between rodents and primates, whereas RUNX1 was only expressed in the UB tip, not in the RV, CSB, or SSB of cynomolgus monkeys, suggesting a species differences. We further evaluated the roles of RUNX1 using two different conditional knockout mice: Runx1f/f:HoxB7-Cre and Runx1f/f:R26-CreERT2 and found no abnormalities in the kidney. Our findings showed that RUNX1, which is mainly expressed in the UB tip, is not essential for kidney development.
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Subunidad alfa 2 del Factor de Unión al Sitio Principal , Riñón , Animales , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Riñón/metabolismo , Riñón/embriología , Riñón/crecimiento & desarrollo , Ratones , Macaca fascicularis , Regulación del Desarrollo de la Expresión Génica , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 3 del Factor de Unión al Sitio Principal/metabolismo , Subunidad alfa 3 del Factor de Unión al Sitio Principal/genética , Subunidades alfa del Factor de Unión al Sitio Principal/metabolismo , Subunidades alfa del Factor de Unión al Sitio Principal/genética , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
IGLL5 is shown to be located near super-enhancer (SE) in B-cell tumors, and this gene is frequently mutated and a target of translocation in B-cell tumors. These results suggest roles of the IGLL5 in tumorigenesis; however, its functional properties have been unclear. We found that two mature B-cell lymphoma cell lines expressed IGLL5 mRNA with Cλ1 segment. JQ1 treatment resulted in down-expression of IGLL5, indicating that IGLL5 is controlled by SE. IGLL5 knockdown induced cell death with down-expression of MYC. Our results suggested that IGLL5 might have a role in survival of mature B-cell tumors and involvement in MYC expression. (100 words).
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In many cancers, mortality is associated with the emergence of relapse with multidrug resistance (MDR). Thus far, the investigation of cancer relapse mechanisms has largely focused on acquired genetic mutations. Using acute myeloid leukemia (AML) patient-derived xenografts (PDX), we systematically elucidated a basis of MDR and identified drug sensitivity in relapsed AML. We derived pharmacologic sensitivity for 22 AML PDX models using dynamic BH3 profiling (DBP), together with genomics and transcriptomics. Using in vivo acquired resistant PDXs, we found that resistance to unrelated, narrowly targeted agents in distinct PDXs was accompanied by broad resistance to drugs with disparate mechanisms. Moreover, baseline mitochondrial apoptotic priming was consistently reduced regardless of the class of drug-inducing selection. By applying DBP, we identified drugs showing effective in vivo activity in resistant models. This study implies evasion of apoptosis drives drug resistance and demonstrates the feasibility of the DBP approach to identify active drugs for patients with relapsed AML. SIGNIFICANCE: Acquired resistance to targeted therapy remains challenging in AML. We found that reduction in mitochondrial priming and common transcriptomic signatures was a conserved mechanism of acquired resistance across different drug classes in vivo. Drugs active in vivo can be identified even in the multidrug resistant state by DBP.
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Apoptosis , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Leucemia Mieloide Aguda , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/genética , Humanos , Apoptosis/efectos de los fármacos , Animales , Ratones , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Resistencia a Múltiples Medicamentos/genética , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Células Precursoras de Granulocitos/efectos de los fármacos , Células Precursoras de Granulocitos/patología , Antineoplásicos/farmacología , Antineoplásicos/uso terapéuticoRESUMEN
A well-documented Achilles heel of current cancer immunotherapy approaches is T cell exhaustion within solid tumor tissues. The proinflammatory cytokine interleukin (IL)-23 has been utilized to augment chimeric antigen receptor (CAR) T cell survival and tumor immunity. However, in-depth interrogation of molecular events downstream of IL-23/IL-23 receptor signaling is hampered by a paucity of suitable cell models. The current study investigates the differential contribution of IL-2 and IL-23 to the maintenance and differentiation of the IL-23 responsive Kit225 T-cell line. We observed that IL-23 enhanced cellular fitness and survival but was insufficient to drive proliferation. IL-23 rapidly induced phosphorylation of STAT1, STAT3, and STAT4, and messenger RNA expression of IL17A, the archetypal effector cytokine of T helper 17 (Th17) cells, but not their lineage markers RORC and NCR1. These observations suggest that IL-23 endowed Th17/ILC3-like effector function but did not promote their differentiation. In contrast, spontaneous differentiation of Kit225 cells toward a Th17/ILC3-like phenotype was induced by prolonged IL-2 withdrawal. This was marked by strongly elevated basal IL17A and IL17F expression and the secretion of IL-17. Together, our data present Kit225 cells as a valuable model for studying the interplay between cytokines and their contribution to T cell survival, proliferation, and differentiation.
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Diferenciación Celular , Interleucina-23 , Interleucina-2 , Células Th17 , Humanos , Línea Celular , Proliferación Celular , Supervivencia Celular , Interleucina-17/metabolismo , Interleucina-17/inmunología , Interleucina-2/farmacología , Interleucina-23/metabolismo , Interleucina-23/inmunología , Transducción de Señal , Células Th17/inmunologíaRESUMEN
Cancer is a very rare event at the cellular level, although it is a common disease at the body level as one third of humans die of cancer. A small subset of cells in the body harbor the cellular features that constitute a permissive window for a particular genetic change to induce cancer. The significance of a permissive window is ironically best shown by a large number of failures in generating the animal model for acute myeloid leukemia (AML) with t(8;21). Over the decades, the RUNX1-ETO fusion gene created by t(8;21) has been introduced into various types of hematopoietic cells, largely at adult stage, in mice; however, all the previous attempts failed to generate tractable AML models. In stark contrast, we recently succeeded in inducing AML with the clinical features seen in human patients by specifically introducing RUNX1-ETO in childhood hematopoietic stem cells (HSCs). This result in mice is consistent with adolescent and young adult (AYA) onset in human t(8;21) patients, and suggests that childhood HSCs constitute the permissive window for RUNX1-ETO leukemogenesis. If loss of a permissive window is induced pharmacologically, cancer cells might be selectively targeted. Such a permissive window modifier may serve as a novel therapeutic drug.
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Subunidad alfa 2 del Factor de Unión al Sitio Principal , Leucemia Mieloide Aguda , Humanos , Ratones , Animales , Adolescente , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Translocación Genética , Leucemia Mieloide Aguda/genética , Células Madre HematopoyéticasRESUMEN
Mesenchymal chondrosarcoma affects adolescents and young adults, and most cases usually have the HEY1::NCOA2 fusion gene. However, the functional role of HEY1-NCOA2 in the development and progression of mesenchymal chondrosarcoma remains largely unknown. This study aimed to clarify the functional role of HEY1-NCOA2 in transformation of the cell of origin and induction of typical biphasic morphology of mesenchymal chondrosarcoma. We generated a mouse model for mesenchymal chondrosarcoma by introducing HEY1-NCOA2 into mouse embryonic superficial zone (eSZ) followed by subcutaneous transplantation into nude mice. HEY1-NCOA2 expression in eSZ cells successfully induced subcutaneous tumors in 68.9% of recipients, showing biphasic morphologies and expression of Sox9, a master regulator of chondrogenic differentiation. ChIP sequencing analyses indicated frequent interaction between HEY1-NCOA2 binding peaks and active enhancers. Runx2, which is important for differentiation and proliferation of the chondrocytic lineage, is invariably expressed in mouse mesenchymal chondrosarcoma, and interaction between HEY1-NCOA2 and Runx2 is observed using NCOA2 C-terminal domains. Although Runx2 knockout resulted in significant delay in tumor onset, it also induced aggressive growth of immature small round cells. Runx3, which is also expressed in mesenchymal chondrosarcoma and interacts with HEY1-NCOA2, replaced the DNA-binding property of Runx2 only in part. Treatment with the HDAC inhibitor panobinostat suppressed tumor growth both in vitro and in vivo, abrogating expression of genes downstream of HEY1-NCOA2 and Runx2. In conclusion, HEY1::NCOA2 expression modulates the transcriptional program in chondrogenic differentiation, affecting cartilage-specific transcription factor functions.
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Neoplasias Óseas , Condrosarcoma Mesenquimal , Proteínas de Fusión Oncogénica , Animales , Ratones , Neoplasias Óseas/genética , Neoplasias Óseas/patología , Diferenciación Celular , Condrosarcoma Mesenquimal/genética , Condrosarcoma Mesenquimal/metabolismo , Condrosarcoma Mesenquimal/patología , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Ratones Desnudos , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismoRESUMEN
Adenosine-to-inosine RNA editing, which is catalyzed by adenosine deaminases acting on RNA (ADAR) family of enzymes, ADAR1 and ADAR2, has been shown to contribute to multiple cancers. However, other than the chronic myeloid leukemia blast crisis, relatively little is known about its role in other types of hematological malignancies. Here, we found that ADAR2, but not ADAR1 and ADAR3, was specifically downregulated in the core-binding factor (CBF) acute myeloid leukemia (AML) with t(8;21) or inv(16) translocations. In t(8;21) AML, RUNX1-driven transcription of ADAR2 was repressed by the RUNX1-ETO additional exon 9a fusion protein in a dominant-negative manner. Further functional studies confirmed that ADAR2 could suppress leukemogenesis specifically in t(8;21) and inv16 AML cells dependent on its RNA editing capability. Expression of 2 exemplary ADAR2-regulated RNA editing targets coatomer subunit α and component of oligomeric Golgi complex 3 inhibits the clonogenic growth of human t(8;21) AML cells. Our findings support a hitherto, unappreciated mechanism leading to ADAR2 dysregulation in CBF AML and highlight the functional relevance of loss of ADAR2-mediated RNA editing to CBF AML.
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Factores de Unión al Sitio Principal , Leucemia Mieloide Aguda , Humanos , Regulación hacia Abajo , Factores de Unión al Sitio Principal/metabolismo , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Edición de ARN , Adenosina Desaminasa/genética , Adenosina Desaminasa/metabolismo , Leucemia Mieloide Aguda/genética , Adenosina/metabolismoRESUMEN
The DNA repair machinery exists to protect cells from daily genetic insults by orchestrating multiple intrinsic and extrinsic factors. One such factor recently identified is the Runt-related transcription factor (RUNX) family, a group of proteins that act as a master transcriptional regulator for multiple biological functions such as embryonic development, stem cell behaviors, and oncogenesis. A significant number of studies in the past decades have delineated the involvement of RUNX proteins in DNA repair. Alterations in RUNX genes cause organ failure and predisposition to cancers, as seen in patients carrying mutations in the other well-established DNA repair genes. Herein, we review the currently existing findings and provide new insights into transcriptional and non-transcriptional multifaceted regulation of DNA repair by RUNX family proteins.
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Subunidades alfa del Factor de Unión al Sitio Principal , Neoplasias , Femenino , Embarazo , Humanos , Subunidades alfa del Factor de Unión al Sitio Principal/genética , Subunidades alfa del Factor de Unión al Sitio Principal/metabolismo , Factores de Transcripción/metabolismo , Genoma , Regulación de la Expresión Génica , Neoplasias/genéticaRESUMEN
Telomeres are specialized nucleoprotein structures at the ends of linear chromosomes. The progressive shortening of steady-state telomere length in normal human somatic cells is a promising biomarker for age-associated diseases. However, there remain substantial challenges in quantifying telomere length due to the lack of high-throughput method with nucleotide resolution for individual telomere. Here, we describe a workflow to capture telomeres using newly designed telobaits in human culture cell lines as well as clinical patient samples and measure their length accurately at nucleotide resolution using single-molecule real-time (SMRT) sequencing. Our results also reveal the extreme heterogeneity of telomeric variant sequences (TVSs) that are dispersed throughout the telomere repeat region. The presence of TVSs disrupts the continuity of the canonical (5'-TTAGGG-3')n telomere repeats, which affects the binding of shelterin complexes at the chromosomal ends and telomere protection. These findings may have profound implications in human aging and diseases.
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Complejo Shelterina , Telómero , Humanos , Telómero/genética , EnvejecimientoRESUMEN
A cis-regulatory genetic element which targets gene expression to stem cells, termed stem cell enhancer, serves as a molecular handle for stem cell-specific genetic engineering. Here we show the generation and characterization of a tamoxifen-inducible CreERT2 transgenic (Tg) mouse employing previously identified hematopoietic stem cell (HSC) enhancer for Runx1, eR1 (+24 m). Kinetic analysis of labeled cells after tamoxifen injection and transplantation assays revealed that eR1-driven CreERT2 activity marks dormant adult HSCs which slowly but steadily contribute to unperturbed hematopoiesis. Fetal and child HSCs that are uniformly or intermediately active were also efficiently targeted. Notably, a gene ablation at distinct developmental stages, enabled by this system, resulted in different phenotypes. Similarly, an oncogenic Kras induction at distinct ages caused different spectrums of malignant diseases. These results demonstrate that the eR1-CreERT2 Tg mouse serves as a powerful resource for the analyses of both normal and malignant HSCs at all developmental stages.
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Células Madre Adultas , Células Madre Hematopoyéticas , Animales , Ratones , Cinética , Feto , Ingeniería Genética , Ratones Transgénicos , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genéticaRESUMEN
BACKGROUND: Currently available anti-leukemia drugs have shown limited success in the treatment of acute myeloid leukemia (AML) due to their poor access to bone marrow niche supporting leukemic cell proliferation. RESULTS: Herein, we report a bone marrow-targetable green tea catechin-based micellar nanocomplex for synergistic AML therapy. The nanocomplex was found to synergistically amplify the anti-leukemic potency of sorafenib via selective disruption of pro-survival mTOR signaling. In vivo biodistribution study demonstrated about 11-fold greater bone marrow accumulation of the nanocomplex compared to free sorafenib. In AML patient-derived xenograft (AML-PDX) mouse model, administration of the nanocomplex effectively eradicated bone marrow-residing leukemic blasts and improved survival rates without noticeable off-target toxicity. CONCLUSION: This study may provide insights into the rational design of nanomedicine platforms enabling bone marrow-targeted delivery of therapeutic agents for the treatment of AML and other bone marrow diseases.
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Catequina , Leucemia Mieloide Aguda , Ratones , Animales , Humanos , Médula Ósea , Catequina/farmacología , Micelas , Sorafenib , Distribución Tisular , Leucemia Mieloide Aguda/tratamiento farmacológico , Modelos Animales de Enfermedad , TéRESUMEN
The transcription factor MYB is a crucial regulator of hematopoietic stem and progenitor cells. However, the nature of lineage-specific enhancer usage of the Myb gene is largely unknown. We identify the Myb -68 enhancer, a regulatory element which marks basophils and mast cells. Using the Myb -68 enhancer activity, we show a population of granulocyte-macrophage progenitors with higher potential to differentiate into basophils and mast cells. Single cell RNA-seq demonstrates the differentiation trajectory is continuous from progenitors to mature basophils in vivo, characterizes bone marrow cells with a gene signature of mast cells, and identifies LILRB4 as a surface marker of basophil maturation. Together, our study leads to a better understanding of how MYB expression is regulated in a lineage-associated manner, and also shows how a combination of lineage-related reporter mice and single-cell transcriptomics can overcome the rarity of target cells and enhance our understanding of gene expression programs that control cell differentiation in vivo.
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Basófilos , Hematopoyesis , Ratones , Animales , Recuento de Leucocitos , Diferenciación Celular/genética , Células Madre/metabolismoRESUMEN
We reported earlier that IQGAP3 is an important stem cell factor in rapidly proliferating isthmus stem cells in the stomach and that IQGAP3 expression is robustly induced in terminally differentiated chief cells and de-differentiated cells following tissue damage. The elevated IQGAP3 expression in cancer and its association with metastasis suggest a fundamental role for IQGAP3 in proliferating cancer stem cells. What causes IQGAP3 upregulation in cancer is unclear. Here, we show that IGF2BP1 and IQGAP3 expression levels are highest in the blastocyst, with both decreasing during adulthood. This suggests that IQGAP3, like IGF2BP1, is an early developmental gene that is aberrantly upregulated upon re-expression of IGF2BP1 during carcinogenesis. IGF2BP1 binds and stabilizes m6A-modified IQGAP3 transcripts. Downstream targets of IGF2BP1, namely SRF and FOXM1, also upregulate IQGAP3 expression. These multiple layers of IQGAP3 regulation, which may safeguard against inappropriate stem cell proliferation, present additional drug targets to inhibit IQGAP3-driven malignant growth.
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Self-renewal and differentiation are tightly controlled to maintain haematopoietic stem cell (HSC) homeostasis in the adult bone marrow1,2. During fetal development, expansion of HSCs (self-renewal) and production of differentiated haematopoietic cells (differentiation) are both required to sustain the haematopoietic system for body growth3,4. However, it remains unclear how these two seemingly opposing tasks are accomplished within the short embryonic period. Here we used in vivo genetic tracing in mice to analyse the formation of HSCs and progenitors from intra-arterial haematopoietic clusters, which contain HSC precursors and express the transcription factor hepatic leukaemia factor (HLF). Through kinetic study, we observed the simultaneous formation of HSCs and defined progenitors-previously regarded as descendants of HSCs5-from the HLF+ precursor population, followed by prompt formation of the hierarchical haematopoietic population structure in the fetal liver in an HSC-independent manner. The transcription factor EVI1 is heterogeneously expressed within the precursor population, with EVI1hi cells being predominantly localized to intra-embryonic arteries and preferentially giving rise to HSCs. By genetically manipulating EVI1 expression, we were able to alter HSC and progenitor output from precursors in vivo. Using fate tracking, we also demonstrated that fetal HSCs are slowly used to produce short-term HSCs at late gestation. These data suggest that fetal HSCs minimally contribute to the generation of progenitors and functional blood cells before birth. Stem cell-independent pathways during development thus offer a rational strategy for the rapid and simultaneous growth of tissues and stem cell pools.
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Linaje de la Célula , Feto , Células Madre Hematopoyéticas , Hígado , Animales , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Médula Ósea , Diferenciación Celular , Autorrenovación de las Células , Rastreo Celular , Femenino , Feto/citología , Células Madre Hematopoyéticas/citología , Hígado/citología , Proteína del Locus del Complejo MDS1 y EV11/metabolismo , Ratones , Embarazo , Factores de Transcripción/metabolismoRESUMEN
Recent genetic lineage tracing studies reveal heterogeneous origins of vascular endothelial cells and pericytes in the developing brain vasculature, despite classical experimental evidence for a mesodermal origin. Here we provide evidence through a genetic lineage tracing experiment that cephalic paraxial mesodermal cells give rise to endothelial cells and pericytes in the developing mouse brain. We show that Hepatic leukemia factor (Hlf) is transiently expressed by cephalic paraxial mesenchyme at embryonic day (E) 8.0-9.0 and the genetically marked E8.0 Hlf-expressing cells mainly contribute to the developing brain vasculature. Interestingly, the genetically marked E10.5 Hlf-expressing cells, which have been previously reported to contain embryonic hematopoietic stem cells, fail to contribute to the vascular cells. Combined, our genetic lineage tracing data demonstrate that a transient expression of Hlf marks a cephalic paraxial mesenchyme contributing to the developing brain vasculature. This article has an associated First Person interview with the first author of the paper.
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Células Endoteliales , Leucemia , Animales , Encéfalo , Humanos , Leucemia/metabolismo , Mesodermo , Ratones , Células MadreRESUMEN
Down syndrome (DS) is a common congenital disorder caused by trisomy 21. Due to the increase in maternal age with population aging and advances in medical treatment for fatal complications in their early childhood, the prevalence and life expectancy of DS individuals have greatly increased. Despite this rise in the number of DS adults, their hematological status remains poorly examined. Here, we report that three hematological abnormalities, leukopenia, macrocytosis, and thrombocytopenia, develop as adult DS-associated features. Multi- and uni-variate analyses on hematological data collected from 51 DS and 60 control adults demonstrated that young adults with DS are at significantly higher risk of (i) myeloid-dominant leukopenia, (ii) macrocytosis characterized by high mean cell volume (MCV) of erythrocytes, and (iii) lower platelet counts than the control. Notably, these features were more pronounced with age. Further analyses on DS adults would provide a deeper understanding and novel research perspectives for multiple aging-related disorders in the general population.
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Síndrome de Down , Enfermedades Hematológicas , Leucopenia , Trombocitopenia , Preescolar , Síndrome de Down/complicaciones , Humanos , Leucopenia/complicaciones , Trisomía , Adulto JovenRESUMEN
Mammary gland homeostasis is maintained by adult tissue stem-progenitor cells residing within the luminal and basal epithelia. Dysregulation of mammary stem cells is a key mechanism for cancer development. However, stem cell characterization is challenging because reporter models using cell-specific promoters do not fully recapitulate the mammary stem cell populations. We previously found that a 270-basepair Runx1 enhancer element, named eR1, marked stem cells in the blood and stomach. Here, we identified eR1 activity in a rare subpopulation of the ERα-negative luminal epithelium in mouse mammary glands. Lineage-tracing using an eR1-CreERT2 mouse model revealed that eR1+ luminal cells generated the entire luminal lineage and milk-secreting alveoli-eR1 therefore specifically marks lineage-restricted luminal stem cells. eR1-targeted-conditional knockout of Runx1 led to the expansion of luminal epithelial cells, accompanied by elevated ERα expression. Our findings demonstrate a definitive role for Runx1 in the regulation of the eR1-positive luminal stem cell proliferation during mammary homeostasis. Our findings identify a mechanistic link for Runx1 in stem cell proliferation and its dysregulation in breast cancer. Runx1 inactivation is therefore likely to be an early hit in the cell-of-origin of ERα+ luminal type breast cancer.