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1.
Nature ; 598(7880): 327-331, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34588693

RESUMEN

Haematopoiesis in the bone marrow (BM) maintains blood and immune cell production throughout postnatal life. Haematopoiesis first emerges in human BM at 11-12 weeks after conception1,2, yet almost nothing is known about how fetal BM (FBM) evolves to meet the highly specialized needs of the fetus and newborn. Here we detail the development of FBM, including stroma, using multi-omic assessment of mRNA and multiplexed protein epitope expression. We find that the full blood and immune cell repertoire is established in FBM in a short time window of 6-7 weeks early in the second trimester. FBM promotes rapid and extensive diversification of myeloid cells, with granulocytes, eosinophils and dendritic cell subsets emerging for the first time. The substantial expansion of B lymphocytes in FBM contrasts with fetal liver at the same gestational age. Haematopoietic progenitors from fetal liver, FBM and cord blood exhibit transcriptional and functional differences that contribute to tissue-specific identity and cellular diversification. Endothelial cell types form distinct vascular structures that we show are regionally compartmentalized within FBM. Finally, we reveal selective disruption of B lymphocyte, erythroid and myeloid development owing to a cell-intrinsic differentiation bias as well as extrinsic regulation through an altered microenvironment in Down syndrome (trisomy 21).


Asunto(s)
Células de la Médula Ósea/citología , Médula Ósea , Síndrome de Down/sangre , Síndrome de Down/inmunología , Feto/citología , Hematopoyesis , Sistema Inmunológico/citología , Linfocitos B/citología , Células Dendríticas/citología , Síndrome de Down/metabolismo , Síndrome de Down/patología , Células Endoteliales/patología , Eosinófilos/citología , Células Eritroides/citología , Granulocitos/citología , Humanos , Inmunidad , Células Mieloides/citología , Células del Estroma/citología
2.
Blood ; 140(1): 38-44, 2022 07 07.
Artículo en Inglés | MEDLINE | ID: mdl-35421218

RESUMEN

CD19-directed immunotherapies have revolutionized the treatment of advanced B-cell acute lymphoblastic leukemia (B-ALL). Despite initial impressive rates of complete remission (CR) many patients ultimately relapse. Patients with B-ALL successfully treated with CD19-directed T cells eventually relapse, which, coupled with the early onset of CD22 expression during B-cell development, suggests that preexisting CD34+CD22+CD19- (pre)-leukemic cells represent an "early progenitor origin-related" mechanism underlying phenotypic escape to CD19-directed immunotherapies. We demonstrate that CD22 expression precedes CD19 expression during B-cell development. CD34+CD19-CD22+ cells are found in diagnostic and relapsed bone marrow samples of ∼70% of patients with B-ALL, and their frequency increases twofold in patients with B-ALL in CR after CD19 CAR T-cell therapy. The median of CD34+CD19-CD22+ cells before treatment was threefold higher in patients in whom B-ALL relapsed after CD19-directed immunotherapy (median follow-up, 24 months). Fluorescence in situ hybridization analysis in flow-sorted cell populations and xenograft modeling revealed that CD34+CD19-CD22+ cells harbor the genetic abnormalities present at diagnosis and initiate leukemogenesis in vivo. Our data suggest that preleukemic CD34+CD19-CD22+ progenitors underlie phenotypic escape after CD19-directed immunotherapies and reinforce ongoing clinical studies aimed at CD19/CD22 dual targeting as a strategy for reducing CD19- relapses. The implementation of CD34/CD19/CD22 immunophenotyping in clinical laboratories for initial diagnosis and subsequent monitoring of patients with B-ALL during CD19-targeted therapy is encouraged.


Asunto(s)
Antígenos CD19 , Linfoma de Burkitt , Antígenos CD34 , Linfocitos B , Humanos , Inmunofenotipificación , Hibridación Fluorescente in Situ , Recurrencia , Lectina 2 Similar a Ig de Unión al Ácido Siálico
3.
Blood ; 134(13): 1059-1071, 2019 09 26.
Artículo en Inglés | MEDLINE | ID: mdl-31383639

RESUMEN

Human lymphopoiesis is a dynamic lifelong process that starts in utero 6 weeks postconception. Although fetal B-lymphopoiesis remains poorly defined, it is key to understanding leukemia initiation in early life. Here, we provide a comprehensive analysis of the human fetal B-cell developmental hierarchy. We report the presence in fetal tissues of 2 distinct CD19+ B-progenitors, an adult-type CD10+ve ProB-progenitor and a new CD10-ve PreProB-progenitor, and describe their molecular and functional characteristics. PreProB-progenitors and ProB-progenitors appear early in the first trimester in embryonic liver, followed by a sustained second wave of B-progenitor development in fetal bone marrow (BM), where together they form >40% of the total hematopoietic stem cell/progenitor pool. Almost one-third of fetal B-progenitors are CD10-ve PreProB-progenitors, whereas, by contrast, PreProB-progenitors are almost undetectable (0.53% ± 0.24%) in adult BM. Single-cell transcriptomics and functional assays place fetal PreProB-progenitors upstream of ProB-progenitors, identifying them as the first B-lymphoid-restricted progenitor in human fetal life. Although fetal BM PreProB-progenitors and ProB-progenitors both give rise solely to B-lineage cells, they are transcriptionally distinct. As with their fetal counterparts, adult BM PreProB-progenitors give rise only to B-lineage cells in vitro and express the expected B-lineage gene expression program. However, fetal PreProB-progenitors display a distinct, ontogeny-related gene expression pattern that is not seen in adult PreProB-progenitors, and they share transcriptomic signatures with CD10-ve B-progenitor infant acute lymphoblastic leukemia blast cells. These data identify PreProB-progenitors as the earliest B-lymphoid-restricted progenitor in human fetal life and suggest that this fetal-restricted committed B-progenitor might provide a permissive cellular context for prenatal B-progenitor leukemia initiation.


Asunto(s)
Feto/citología , Linfopoyesis , Neprilisina/análisis , Células Precursoras de Linfocitos B/citología , Adulto , Médula Ósea/embriología , Médula Ósea/metabolismo , Células Cultivadas , Feto/embriología , Feto/metabolismo , Regulación del Desarrollo de la Expresión Génica , Humanos , Hígado/embriología , Hígado/metabolismo , Neprilisina/genética , Células Precursoras de Linfocitos B/metabolismo , Transcriptoma
4.
Clin Immunol ; 183: 8-16, 2017 10.
Artículo en Inglés | MEDLINE | ID: mdl-28645875

RESUMEN

The ontogeny of the natural, public IgM repertoire remains incompletely explored. Here, high-resolution immunogenetic analysis of B cells from (unrelated) fetal, child, and adult samples, shows that although fetal liver (FL) and bone marrow (FBM) IgM repertoires are equally diversified, FL is the main source of IgM natural immunity during the 2nd trimester. Strikingly, 0.25% of all prenatal clonotypes, comprising 18.7% of the expressed repertoire, are shared with the postnatal samples, consistent with persisting fetal IgM+ B cells being a source of natural IgM repertoire in adult life. Further, the origins of specific stereotypic IgM+ B cell receptors associated with chronic lymphocytic leukemia, can be traced back to fetal B cell lymphopoiesis, suggesting that persisting fetal B cells can be subject to malignant transformation late in life. Overall, these novel data provide unique insights into the ontogeny of physiological and malignant B lymphopoiesis that spans the human lifetime.


Asunto(s)
Linfocitos B/inmunología , Médula Ósea/inmunología , Feto/inmunología , Cadenas Pesadas de Inmunoglobulina/genética , Inmunoglobulina M/genética , Leucemia Linfocítica Crónica de Células B/genética , Hígado/inmunología , Linfopoyesis/genética , Receptores de Antígenos de Linfocitos B/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Cadenas Pesadas de Inmunoglobulina/inmunología , Inmunoglobulina M/inmunología , Leucemia Linfocítica Crónica de Células B/inmunología , Linfopoyesis/inmunología , Receptores de Antígenos de Linfocitos B/inmunología , Análisis de Secuencia de ADN
6.
Cell Rep ; 36(11): 109698, 2021 09 14.
Artículo en Inglés | MEDLINE | ID: mdl-34525349

RESUMEN

Human hematopoiesis is a dynamic process that starts in utero 18-21 days post-conception. Understanding the site- and stage-specific variation in hematopoiesis is important if we are to understand the origin of hematological disorders, many of which occur at specific points in the human lifespan. To unravel how the hematopoietic stem/progenitor cell (HSPC) compartment changes during human ontogeny and the underlying gene regulatory mechanisms, we compare 57,489 HSPCs from 5 different tissues spanning 4 developmental stages through the human lifetime. Single-cell transcriptomic analysis identifies significant site- and developmental stage-specific transitions in cellular architecture and gene regulatory networks. Hematopoietic stem cells show progression from cycling to quiescence and increased inflammatory signaling during ontogeny. We demonstrate the utility of this dataset for understanding aberrant hematopoiesis through comparison to two cancers that present at distinct time points in postnatal life-juvenile myelomonocytic leukemia, a childhood cancer, and myelofibrosis, which classically presents in older adults.


Asunto(s)
Linaje de la Célula/genética , Redes Reguladoras de Genes/genética , Células Madre Hematopoyéticas/metabolismo , Diferenciación Celular , Hematopoyesis , Células Madre Hematopoyéticas/citología , Humanos , Análisis de Secuencia de ARN , Transducción de Señal , Análisis de la Célula Individual , Transcriptoma
7.
Nat Commun ; 12(1): 6905, 2021 11 25.
Artículo en Inglés | MEDLINE | ID: mdl-34824279

RESUMEN

Although 90% of children with acute lymphoblastic leukemia (ALL) are now cured, the prognosis for infant-ALL remains dismal. Infant-ALL is usually caused by a single genetic hit that arises in utero: an MLL/KMT2A gene rearrangement (MLL-r). This is sufficient to induce a uniquely aggressive and treatment-refractory leukemia compared to older children. The reasons for disparate outcomes in patients of different ages with identical driver mutations are unknown. Using the most common MLL-r in infant-ALL, MLL-AF4, as a disease model, we show that fetal-specific gene expression programs are maintained in MLL-AF4 infant-ALL but not in MLL-AF4 childhood-ALL. We use CRISPR-Cas9 gene editing of primary human fetal liver hematopoietic cells to produce a t(4;11)/MLL-AF4 translocation, which replicates the clinical features of infant-ALL and drives infant-ALL-specific and fetal-specific gene expression programs. These data support the hypothesis that fetal-specific gene expression programs cooperate with MLL-AF4 to initiate and maintain the distinct biology of infant-ALL.


Asunto(s)
Feto , Regulación Neoplásica de la Expresión Génica , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Animales , Sistemas CRISPR-Cas , Proteínas de Unión al ADN , Femenino , Edición Génica , N-Metiltransferasa de Histona-Lisina , Humanos , Hígado , Ratones , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , Proteínas de Fusión Oncogénica/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Factores de Elongación Transcripcional
8.
Leukemia ; 35(1): 90-106, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32242051

RESUMEN

MLL gene rearrangements (MLLr) are a common cause of aggressive, incurable acute lymphoblastic leukemias (ALL) in infants and children, most of which originate in utero. The most common MLLr produces an MLL-AF4 fusion protein. MLL-AF4 promotes leukemogenesis by activating key target genes, mainly through recruitment of DOT1L and increased histone H3 lysine-79 methylation (H3K79me2/3). One key MLL-AF4 target gene is PROM1, which encodes CD133 (Prominin-1). CD133 is a pentaspan transmembrane glycoprotein that represents a potential pan-cancer target as it is found on multiple cancer stem cells. Here we demonstrate that aberrant PROM1/CD133 expression is essential for leukemic cell growth, mediated by direct binding of MLL-AF4. Activation is controlled by an intragenic H3K79me2/3 enhancer element (KEE) leading to increased enhancer-promoter interactions between PROM1 and the nearby gene TAPT1. This dual locus regulation is reflected in a strong correlation of expression in leukemia. We find that in PROM1/CD133 non-expressing cells, the PROM1 locus is repressed by polycomb repressive complex 2 (PRC2) binding, associated with reduced expression of TAPT1, partially due to loss of interactions with the PROM1 locus. Together, these results provide the first detailed analysis of PROM1/CD133 regulation that explains CD133 expression in MLLr ALL.


Asunto(s)
Antígeno AC133/genética , Elementos de Facilitación Genéticos , Regulación Leucémica de la Expresión Génica , Histonas/metabolismo , Proteína de la Leucemia Mieloide-Linfoide/genética , Células Madre Neoplásicas/metabolismo , Proteínas de Fusión Oncogénica/genética , Regiones Promotoras Genéticas , Biomarcadores de Tumor , Línea Celular Tumoral , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Silenciador del Gen , Humanos , Inmunofenotipificación , Leucemia/genética , Leucemia/metabolismo , Modelos Biológicos , Unión Proteica
9.
J Exp Med ; 218(2)2021 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-33416891

RESUMEN

Juvenile myelomonocytic leukemia (JMML) is a poor-prognosis childhood leukemia usually caused by RAS-pathway mutations. The cellular hierarchy in JMML is poorly characterized, including the identity of leukemia stem cells (LSCs). FACS and single-cell RNA sequencing reveal marked heterogeneity of JMML hematopoietic stem/progenitor cells (HSPCs), including an aberrant Lin-CD34+CD38-CD90+CD45RA+ population. Single-cell HSPC index-sorting and clonogenic assays show that (1) all somatic mutations can be backtracked to the phenotypic HSC compartment, with RAS-pathway mutations as a "first hit," (2) mutations are acquired with both linear and branching patterns of clonal evolution, and (3) mutant HSPCs are present after allogeneic HSC transplant before molecular/clinical evidence of relapse. Stem cell assays reveal interpatient heterogeneity of JMML LSCs, which are present in, but not confined to, the phenotypic HSC compartment. RNA sequencing of JMML LSC reveals up-regulation of stem cell and fetal genes (HLF, MEIS1, CNN3, VNN2, and HMGA2) and candidate therapeutic targets/biomarkers (MTOR, SLC2A1, and CD96), paving the way for LSC-directed disease monitoring and therapy in this disease.


Asunto(s)
Células Madre Hematopoyéticas/patología , Leucemia Mielomonocítica Juvenil/patología , Animales , Biomarcadores de Tumor/genética , Línea Celular , Femenino , Humanos , Leucemia Mielomonocítica Juvenil/genética , Masculino , Ratones , Mutación/genética , Células Madre Neoplásicas/patología , Transducción de Señal/genética , Regulación hacia Arriba/genética
10.
Cell Rep ; 18(2): 482-495, 2017 01 10.
Artículo en Inglés | MEDLINE | ID: mdl-28076791

RESUMEN

Understanding the underlying molecular mechanisms of defined cancers is crucial for effective personalized therapies. Translocations of the mixed-lineage leukemia (MLL) gene produce fusion proteins such as MLL-AF4 that disrupt epigenetic pathways and cause poor-prognosis leukemias. Here, we find that at a subset of gene targets, MLL-AF4 binding spreads into the gene body and is associated with the spreading of Menin binding, increased transcription, increased H3K79 methylation (H3K79me2/3), a disruption of normal H3K36me3 patterns, and unmethylated CpG regions in the gene body. Compared to other H3K79me2/3 marked genes, MLL-AF4 spreading gene expression is downregulated by inhibitors of the H3K79 methyltransferase DOT1L. This sensitivity mediates synergistic interactions with additional targeted drug treatments. Therefore, epigenetic spreading and enhanced susceptibility to epidrugs provides a potential marker for better understanding combination therapies in humans.


Asunto(s)
Elementos de Facilitación Genéticos/genética , Leucemia/genética , Leucemia/patología , Metiltransferasas/antagonistas & inhibidores , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , Proteínas de Fusión Oncogénica/metabolismo , Sitios de Unión , Línea Celular Tumoral , Islas de CpG/genética , Metilación de ADN/genética , Regulación Leucémica de la Expresión Génica , Genoma Humano , N-Metiltransferasa de Histona-Lisina , Histonas/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Lisina/metabolismo , Metiltransferasas/metabolismo , Pronóstico , Unión Proteica , Proteínas Proto-Oncogénicas/metabolismo
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