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1.
Nat Rev Cancer ; 23(8): 565-576, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37280427

RESUMEN

Acute lymphoblastic leukaemia (ALL) is the most common cancer of childhood. Here, we map emerging evidence suggesting that children with ALL at the time of diagnosis may have a delayed maturation of the gut microbiome compared with healthy children. This finding may be associated with early-life epidemiological factors previously identified as risk indicators for childhood ALL, including caesarean section birth, diminished breast feeding and paucity of social contacts. The consistently observed deficiency in short-chain fatty-acid-producing bacterial taxa in children with ALL has the potential to promote dysregulated immune responses and to, ultimately, increase the risk of transformation of preleukaemic clones in response to common infectious triggers. These data endorse the concept that a microbiome deficit in early life may contribute to the development of the major subtypes of childhood ALL and encourage the notion of risk-reducing microbiome-targeted intervention in the future.


Asunto(s)
Microbioma Gastrointestinal , Leucemia-Linfoma Linfoblástico de Células Precursoras , Niño , Humanos , Embarazo , Femenino , Cesárea , Lactancia Materna , Factores de Riesgo
3.
Eur J Cancer ; 172: 146-157, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35772352

RESUMEN

INTRODUCTION: Translation of genome-wide association study (GWAS) findings into preventive approaches is challenged by the identification of the causal risk variants and the understanding of the biological mechanisms by which they act. We present using allelic expression (AE) ratios to perform quantitative case-control analysis as a novel approach to identify risk associations, causal regulatory variants, and target genes. METHODS: Using the breast cancer (BC) risk locus 17q22 to validate this approach, we measured AE ratios in normal breast tissue samples from controls and cases, as well as from unmatched blood samples. Then we used in-silico and in-vitro analysis to map and functionally characterised candidate causal variants. RESULTS: We found a significant shift in the AE patterns of STXBP4 (rs2628315) and COX11 (rs17817901) in the normal breast tissue of cases and healthy controls. Preferential expression of the G-rs2628315 and A-rs17817901 alleles, more often observed in cases, was associated with an increased risk for BC. Analysis of blood samples from cases and controls found a similar association. Furthermore, we identified two putative cis-regulatory variants - rs17817901 and rs8066588 - that affect a miRNA and a transcription factor binding site, respectively. CONCLUSION: We propose causal variants and target genes for the 17q22 BC risk locus and show that using AE ratios in case-control association studies is helpful in identifying risk and mapping causal variants.


Asunto(s)
Neoplasias de la Mama , Estudio de Asociación del Genoma Completo , Alelos , Neoplasias de la Mama/genética , Proteínas Transportadoras de Cobre , Proteínas del Complejo de Cadena de Transporte de Electrón , Femenino , Predisposición Genética a la Enfermedad , Células Germinativas , Humanos , Proteínas Mitocondriales , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , Proteínas de Transporte Vesicular/genética
4.
J Oncol ; 2019: 8941471, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31737072

RESUMEN

Acute lymphoblastic leukaemia (ALL) is the most common cancer of childhood. Although the overall survival of children with ALL is now more than 90%, leukaemia remains one of the leading causes of death from disease. In developed countries, the overall survival of patients with ALL has increased to more than 80%; however, those children cured from ALL still show a significant risk of short- and long-term complications as a consequence of their treatment. Accordingly, there is a need not only to develop new methods of diagnosis and prognosis but also to provide patients with less toxic therapies. MicroRNAs (miRNAs) are small ribonucleic acids (RNA), usually without coding potential, that regulate gene expression by directing their target messenger RNAs (mRNAs) for degradation or translational suppression. In paediatric ALL, several miRNAs have been observed to be overexpressed or underexpressed in patient cohorts compared to healthy individuals, while numerous studies have identified specific miRNAs that can be used as biomarkers to diagnose ALL, classify it into subgroups, and predict prognosis. Likewise, a variety of miRNAs identify as candidate targets for treatment, although there are numerous obstacles to overcome before their clinical use in patients. Here, we summarise the roles played by different miRNAs in childhood leukaemia, focussing primarily on their use as diagnostic tools and potential therapeutic targets, as well as a role in predicting treatment outcome. Finally, we discuss the potential roles of miRNA in immunotherapy and the novel contributions made by gut miRNAs to regulation of the host microbiome.

5.
Mol Cell ; 74(3): 584-597.e9, 2019 05 02.
Artículo en Inglés | MEDLINE | ID: mdl-30905508

RESUMEN

V(D)J recombination is essential to generate antigen receptor diversity but is also a potent cause of genome instability. Many chromosome alterations that result from aberrant V(D)J recombination involve breaks at single recombination signal sequences (RSSs). A long-standing question, however, is how such breaks occur. Here, we show that the genomic DNA that is excised during recombination, the excised signal circle (ESC), forms a complex with the recombinase proteins to efficiently catalyze breaks at single RSSs both in vitro and in vivo. Following cutting, the RSS is released while the ESC-recombinase complex remains intact to potentially trigger breaks at further RSSs. Consistent with this, chromosome breaks at RSSs increase markedly in the presence of the ESC. Notably, these breaks co-localize with those found in acute lymphoblastic leukemia patients and occur at key cancer driver genes. We have named this reaction "cut-and-run" and suggest that it could be a significant cause of lymphocyte genome instability.


Asunto(s)
Inestabilidad Genómica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Translocación Genética/genética , Recombinación V(D)J/genética , Animales , Secuencia de Bases/genética , Células COS , Chlorocebus aethiops , Cromosomas/genética , ADN/genética , Roturas del ADN de Doble Cadena , Células HEK293 , Proteínas de Homeodominio/genética , Humanos , Ratones , Células 3T3 NIH , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Recombinasas/genética
6.
Pediatr Blood Cancer ; 65(11): e27310, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-29968961

RESUMEN

SCL/TAL1 interrupting locus (STIL)-T-cell acute leukaemia (TAL1) fusion genes are present in approximately 11-27% of children with paediatric T-cell acute lymphoblastic leukaemia (T-ALL), but the developmental timing of the rearrangement is still unknown. To investigate whether the fusion gene can be detected in neonatal blood spots (NBSs) from paediatric patients diagnosed with T-cell ALL, we analysed DNA from 38 paediatric patients with T-ALL by nested polymerase chain reaction and electrophoresis. The STIL-TAL1 fusion gene was not detected in NBSs from any of the 38 patients with T-ALL, suggesting that STIL-TAL1 fusion genes are most probably postnatal events in paediatric T-ALL.


Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino
7.
Leukemia ; 32(9): 1984-1993, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-29556024

RESUMEN

Single-cell genetics were used to interrogate clonal complexity and the sequence of mutational events in STIL-TAL1+ T-ALL. Single-cell multicolour FISH was used to demonstrate that the earliest detectable leukaemia subclone contained the STIL-TAL1 fusion and copy number loss of 9p21.3 (CDKN2A/CDKN2B locus), with other copy number alterations including loss of PTEN occurring as secondary subclonal events. In three cases, multiplex qPCR and phylogenetic analysis were used to produce branching evolutionary trees recapitulating the snapshot history of T-ALL evolution in this leukaemia subtype, which confirmed that mutations in key T-ALL drivers, including NOTCH1 and PTEN, were subclonal and reiterative in distinct subclones. Xenografting confirmed that self-renewing or propagating cells were genetically diverse. These data suggest that the STIL-TAL1 fusion is a likely founder or truncal event. Therapies targeting the TAL1 auto-regulatory complex are worthy of further investigation in T-ALL.


Asunto(s)
Evolución Clonal/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Proteína 1 de la Leucemia Linfocítica T Aguda/genética , Adolescente , Adulto , Alelos , Animales , Línea Celular Tumoral , Niño , Preescolar , Modelos Animales de Enfermedad , Estudio de Asociación del Genoma Completo , Xenoinjertos , Humanos , Hibridación Fluorescente in Situ , Lactante , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Reacción en Cadena de la Polimerasa Multiplex , Mutación , Proteínas de Fusión Oncogénica/metabolismo , Fosfohidrolasa PTEN/genética , Polimorfismo de Nucleótido Simple , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Análisis de la Célula Individual , Proteína 1 de la Leucemia Linfocítica T Aguda/metabolismo , Adulto Joven
8.
Biochim Biophys Acta Rev Cancer ; 1868(2): 521-526, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-29056538

RESUMEN

Childhood acute lymphoblastic leukaemia (ALL) with MLL rearrangement (MLL-r) is an aggressive disease still associated with a high mortality rate. Recent investigations have identified co-operating mutations in the RAS pathway and although the functional consequences of these mutations are not yet fully understood, aberrant regulation of RAS pathway signalling at both transcriptional and protein levels is observed. Studies investigating the efficacy of specific inhibitors of this pathway, e.g. MEK-inhibitors, have also achieved encouraging results. In this context, this mini-review summarizes the available data surrounding MLL-r infant ALL with RAS mutation in relation to other well-known features of this intriguing disease.


Asunto(s)
Reordenamiento Génico , Genes ras , N-Metiltransferasa de Histona-Lisina/genética , Mutación , Proteína de la Leucemia Mieloide-Linfoide/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Humanos , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiología , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores
9.
Adv Exp Med Biol ; 962: 217-228, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28299660

RESUMEN

Acute leukaemia is the major subtype of paediatric cancer with a cumulative risk of 1 in 2000 for children up to the age of 15 years. Childhood acute lymphoblastic leukaemia (ALL) is a biologically and clinically diverse disease with distinctive subtypes; multiple chromosomal translocations exist within the subtypes and each carries its own prognostic relevance. The most common chromosome translocation observed is the t(12;21) that results in an in-frame fusion between the first five exons of ETV6 (TEL) and almost the entire coding region of RUNX1 (AML1).The natural history of childhood ALL is almost entirely clinically silent and is well advanced at the point of diagnosis. It has, however, been possible to backtrack this process through molecular analysis of appropriate clinical samples: (i) leukaemic clones in monozygotic twins that are either concordant or discordant for ALL; (ii) archived neonatal blood spots or Guthrie cards from individuals who later developed leukaemia; and (iii) stored, viable cord blood cells.Here, we outline our studies on the aetiology and pathology of childhood ALL that provide molecular evidence for a monoclonal, prenatal origin of ETV6-RUNX1+ leukaemia in monozygotic identical twins. We provide mechanistic support for the concept that altered patterns of infection during early childhood can deliver the necessary promotional drive for the progression of ETV6-RUNX1+ pre-leukaemic cells into a postnatal overt leukaemia.


Asunto(s)
Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Proteínas Proto-Oncogénicas c-ets/genética , Proteínas Represoras/genética , Humanos , Proteínas de Fusión Oncogénica/genética , Gemelos Monocigóticos , Proteína ETS de Variante de Translocación 6
10.
Br J Haematol ; 171(4): 574-84, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26205622

RESUMEN

Infant T-cell acute lymphoblastic leukaemia (iT-ALL) is a very rare and poorly defined entity with a poor prognosis. We assembled a unique series of 13 infants with T-ALL, which allowed us to identify genotypic abnormalities and to investigate prenatal origins. Matched samples (diagnosis/remission) were analysed by single nucleotide polymorphism-array to identify genomic losses and gains. In three cases, we identified a recurrent somatic deletion on chromosome 3. These losses result in the complete deletion of MLF1 and have not previously been described in T-ALL. We observed two cases with an 11p13 deletion (LMO2-related), one of which also harboured a deletion of RB1. Another case presented a large 11q14·1-11q23·2 deletion that included ATM and only five patients (38%) showed deletions of CDKN2A/B. Four cases showed NOTCH1 mutations; in one case FBXW7 was the sole mutation and three cases showed alterations in PTEN. KMT2A rearrangements (KMT2A-r) were detected in three out of 13 cases. For three patients, mutations and copy number alterations (including deletion of PTEN) could be backtracked to birth using neonatal blood spot DNA, demonstrating an in utero origin. Overall, our data indicates that iT-ALL has a diverse but distinctive profile of genotypic abnormalities when compared to T-ALL in older children and adults.


Asunto(s)
Genotipo , Proteínas de Neoplasias/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Edad de Inicio , Aneuploidia , Secuencia de Bases , Proteínas de Ciclo Celular , Cromosomas Humanos Par 11/ultraestructura , Cromosomas Humanos Par 3/ultraestructura , Metilación de ADN , ADN de Neoplasias/genética , Proteínas de Unión al ADN , Femenino , Enfermedades Fetales/genética , Eliminación de Gen , Dosificación de Gen , Genes Relacionados con las Neoplasias , Humanos , Hibridación Fluorescente in Situ , Lactante , Recién Nacido , Masculino , Datos de Secuencia Molecular , Mutación , Polimorfismo de Nucleótido Simple , Leucemia-Linfoma Linfoblástico de Células T Precursoras/embriología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/epidemiología , Regiones Promotoras Genéticas/genética , Proteínas/genética , Eliminación de Secuencia
11.
Blood Cells Mol Dis ; 54(1): 110-5, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25150625

RESUMEN

Associating the risk of childhood acute lymphoblastic leukemia (ALL) with genetic predisposition is still a challenge. Here, we discuss two non-twinned sibs (girl and boy) diagnosed with B-cell precursor (BCP-ALL) and ETV6-RUNX1. BCP-ALL clinical onset occurred 10months apart from each diagnosis. One child is alive in complete continuous remission, whereas, the other relapsed and evolved to death with resistance to ALL treatment. Despite the fact that BCP-ALL with ETV6-RUNX1 usually results in a very good prognosis, the sibs experienced divergent outcomes; a remarkable difference in one child that presented a more aggressive disease was higher leukocytosis associated with IKZF1 deletion. The familial history of cancer and genetic susceptibility was explored. The sibs were absolutely identical in all 17 loci of genes tested; GSTM1, GSTT1, NQO1, TP53, and TP63 were wild-type, whereas at least one copy of the variant allele for IKZF1, ARID5B, PTPRJ and CEBPE was present. The familial pattern of ETV6 was tested by the 12p microsatellite analysis and demonstrated that deletions occurred in one child but not the other, while heterozygous patterns were found in the parents. Altogether, our data suggest that genetic predisposition aligned with chance haa an additive effect in BCP-ALL outcome.


Asunto(s)
Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Predisposición Genética a la Enfermedad , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Hermanos , Adolescente , Preescolar , Resultado Fatal , Femenino , Eliminación de Gen , Sitios Genéticos , Humanos , Factor de Transcripción Ikaros/genética , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico
12.
Nat Genet ; 46(2): 116-25, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24413735

RESUMEN

The ETV6-RUNX1 fusion gene, found in 25% of childhood acute lymphoblastic leukemia (ALL) cases, is acquired in utero but requires additional somatic mutations for overt leukemia. We used exome and low-coverage whole-genome sequencing to characterize secondary events associated with leukemic transformation. RAG-mediated deletions emerge as the dominant mutational process, characterized by recombination signal sequence motifs near breakpoints, incorporation of non-templated sequence at junctions, ∼30-fold enrichment at promoters and enhancers of genes actively transcribed in B cell development and an unexpectedly high ratio of recurrent to non-recurrent structural variants. Single-cell tracking shows that this mechanism is active throughout leukemic evolution, with evidence of localized clustering and reiterated deletions. Integration of data on point mutations and rearrangements identifies ATF7IP and MGA as two new tumor-suppressor genes in ALL. Thus, a remarkably parsimonious mutational process transforms ETV6-RUNX1-positive lymphoblasts, targeting the promoters, enhancers and first exons of genes that normally regulate B cell differentiation.


Asunto(s)
Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Regulación Neoplásica de la Expresión Génica/genética , Reordenamiento Génico/genética , Variación Genética , Proteínas de Homeodominio/genética , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Recombinación Genética/genética , Secuencia de Bases , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Variaciones en el Número de Copia de ADN/genética , Biblioteca de Genes , Genes Supresores de Tumor , Humanos , Datos de Secuencia Molecular , Proteínas Represoras , Análisis de Secuencia de ADN , Eliminación de Secuencia/genética , Factores de Transcripción/genética , Recombinación V(D)J/genética
13.
Blood ; 118(20): 5559-64, 2011 Nov 17.
Artículo en Inglés | MEDLINE | ID: mdl-21960589

RESUMEN

The timing and developmental sequence of events for BCR-ABL1(+) acute lymphoblastic leukemia (ALL), usually associated with IKAROS (IKZF1) deletions, are unknown. We assessed the status of BCR-ABL1 and IKZF1 genes in 2 pairs of monozygotic twins, one pair concordant, the other discordant for Philadelphia chromosome positive (Ph(+)) ALL. The twin pair concordant for ALL shared identical BCR-ABL1 genomic sequence indicative of monoclonal, in utero origin. One twin had IKZF1 deletion and died after transplantation. The other twin had hyperdiploidy, no IKZF1 deletion, and is still in remission 8 years after transplantation. In the twin pair discordant for ALL, neonatal blood spots from both twins harbored the same clonotypic BCR-ABL1 sequence. Low level BCR-ABL1(+) cells were present in the healthy co-twin but lacked the IKZF1 deletion present in the other twin's leukemic cells. The twin with ALL relapsed and died after transplantation. The co-twin remains healthy and leukemia free. These data show that in childhood Ph(+) ALL, BCR-ABL1 gene fusion can be a prenatal and possibly initiating genetic event. In the absence of additional, secondary changes, the leukemic clone remains clinically silent. IKZF1 is a secondary and probable postnatal mutation in these cases, and as a recurrent but alternative copy number change is associated with poor prognosis.


Asunto(s)
Proteínas de Fusión bcr-abl/genética , Factor de Transcripción Ikaros/genética , Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Translocación Genética/genética , Gemelos Monocigóticos/genética , Niño , Preescolar , Puntos de Rotura del Cromosoma , Resultado Fatal , Femenino , Eliminación de Gen , Dosificación de Gen/genética , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Pronóstico
14.
Blood ; 118(18): 4910-8, 2011 Nov 03.
Artículo en Inglés | MEDLINE | ID: mdl-21900195

RESUMEN

ETV6-RUNX1 gene fusion is usually an early, prenatal event in childhood acute lymphoblastic leukemia (ALL). Transformation results in the generation of a persistent (> 14 years) preleukemic clone, which postnatally converts to ALL after the acquisition of necessary secondary genetic alterations. Many cancer cells show some expression of the erythropoietin receptor (EPOR) gene, although the "functionality" of any EPOR complexes and their relevant signaling pathways in nonerythroid cells has not been validated. EPOR mRNA is selectively and ectopically expressed in ETV6-RUNX1(+) ALL, but the presence of a functional EPOR on the cell surface and its role in leukemogenesis driven by ETV6-RUNX1 remains to be identified. Here, we show that ETV6-RUNX1 directly binds the EPOR promoter and that expression of ETV6-RUNX1 alone in normal pre-B cells is sufficient to activate EPOR transcription. We further reveal that murine and human ETV6-RUNX1(+) cells expressing EPOR mRNA have EPO ligand binding activity that correlates with an increased cell survival through activation of the JAK2-STAT5 pathway and up-regulation of antiapoptotic BCL-XL. These data support the contention that ETV6-RUNX1 directly activates ectopic expression of a functional EPOR and provides cell survival signals that may contribute critically to persistence of covert premalignant clones in children.


Asunto(s)
Proteínas de Fusión Oncogénica/fisiología , Células Precursoras de Linfocitos B/fisiología , Receptores de Eritropoyetina/fisiología , Animales , Linaje de la Célula/genética , Linaje de la Célula/fisiología , Supervivencia Celular/genética , Células Cultivadas , Subunidad alfa 2 del Factor de Unión al Sitio Principal , Modelos Animales de Enfermedad , Regulación Leucémica de la Expresión Génica , Células HEK293 , Humanos , Ratones , Ratones Transgénicos , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Lesiones Precancerosas/genética , Lesiones Precancerosas/inmunología , Lesiones Precancerosas/metabolismo , Células Precursoras de Linfocitos B/metabolismo , Receptores de Eritropoyetina/genética , Receptores de Eritropoyetina/metabolismo
16.
Blood ; 115(17): 3553-8, 2010 Apr 29.
Artículo en Inglés | MEDLINE | ID: mdl-20061556

RESUMEN

Chimeric fusion genes are highly prevalent in childhood acute lymphoblastic leukemia (ALL) and are mostly prenatal, early genetic events in the evolutionary trajectory of this cancer. ETV6-RUNX1-positive ALL also has multiple ( approximately 6 per case) copy number alterations (CNAs) as revealed by genome-wide single-nucleotide polymorphism arrays. Recurrent CNAs are probably "driver" events contributing critically to clonal diversification and selection, but at diagnosis, their developmental timing is "buried" in the leukemia's covert natural history. This conundrum can be resolved with twin pairs. We identified and compared CNAs in 5 pairs of monozygotic twins with concordant ETV6-RUNX1-positive ALL and 1 pair discordant for ETV6-RUNX1 positive ALL. We compared, within each pair, CNAs classified as potential "driver" or "passenger" mutations based upon recurrency and, where known, gene function. An average of 5.1 (range 3-11) CNAs (excluding immunoglobulin/T-cell receptor alterations) were identified per case. All "driver" CNAs (total of 32) were distinct within each of the 5 twin pairs with concordant ALL. "Driver" CNAs in another twin with ALL were all absent in the shared ETV6-RUNX1-positive preleukemic clone of her healthy co-twin. These data place all "driver" CNAs secondary to the prenatal gene fusion event and most probably postnatal in the sequential, molecular pathogenesis of ALL.


Asunto(s)
Dosificación de Gen , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Gemelos Monocigóticos , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Femenino , Humanos , Masculino , Mutación , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo
17.
Proc Natl Acad Sci U S A ; 106(42): 17882-5, 2009 Oct 20.
Artículo en Inglés | MEDLINE | ID: mdl-19822752

RESUMEN

Rare cases of possible materno-fetal transmission of cancer have been recorded over the past 100 years but evidence for a shared cancer clone has been very limited. We provide genetic evidence for mother to offspring transmission, in utero, of a leukemic cell clone. Maternal and infant cancer clones shared the same unique BCR-ABL1 genomic fusion sequence, indicating a shared, single-cell origin. Microsatellite markers in the infant cancer were all of maternal origin. Additionally, the infant, maternally-derived cancer cells had a major deletion on one copy of chromosome 6p that included deletion of HLA alleles that were not inherited by the infant (i.e., foreign to the infant), suggesting a possible mechanism for immune evasion.


Asunto(s)
Intercambio Materno-Fetal/genética , Intercambio Materno-Fetal/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/complicaciones , Complicaciones Neoplásicas del Embarazo/genética , Complicaciones Neoplásicas del Embarazo/inmunología , Adulto , Secuencia de Bases , ADN de Neoplasias/genética , Femenino , Genes abl , Antígenos HLA/genética , Humanos , Lactante , Pérdida de Heterocigocidad , Repeticiones de Microsatélite , Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/inmunología , Embarazo , ARN Mensajero/genética , ARN Neoplásico/genética
18.
J Clin Invest ; 119(4): 826-36, 2009 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19287094

RESUMEN

Chromosome translocation to generate the TEL-AML1 (also known as ETV6-RUNX1) chimeric fusion gene is a frequent and early or initiating event in childhood acute lymphoblastic leukemia (ALL). Our starting hypothesis was that the TEL-AML1 protein generates and maintains preleukemic clones and that conversion to overt disease requires secondary genetic changes, possibly in the context of abnormal immune responses. Here, we show that a murine B cell progenitor cell line expressing inducible TEL-AML1 proliferates at a slower rate than parent cells but is more resistant to further inhibition of proliferation by TGF-beta. This facilitates the competitive expansion of TEL-AML1-expressing cells in the presence of TGF-beta. Further analysis indicated that TEL-AML1 binds to a principal TGF-beta signaling target, Smad3, and compromises its ability to activate target promoters. In mice expressing a TEL-AML1 transgene, early, pre-pro-B cells were increased in number and also showed reduced sensitivity to TGF-beta-mediated inhibition of proliferation. Moreover, expression of TEL-AML1 in human cord blood progenitor cells led to the expansion of a candidate preleukemic stem cell population that had an early B lineage phenotype (CD34+CD38-CD19+) and a marked growth advantage in the presence of TGF-beta. Collectively, these data suggest a plausible mechanism by which dysregulated immune responses to infection might promote the malignant evolution of TEL-AML1-expressing preleukemic clones.


Asunto(s)
Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Fusión de Oncogenes , Proteínas de Fusión Oncogénica/genética , Células Precursoras de Linfocitos B/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Animales , Línea Celular , Proliferación Celular , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/genética , Sangre Fetal/citología , Sangre Fetal/metabolismo , Expresión Génica , Hematopoyesis/genética , Humanos , Ratones , Modelos Biológicos , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Transducción de Señal , Proteínas Smad/metabolismo , Células Madre/citología , Células Madre/metabolismo , Transfección
19.
Blood ; 113(3): 646-8, 2009 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-18927438

RESUMEN

Children with Down syndrome (DS) have a greatly increased risk of acute megakaryoblastic leukemia (AMKL) and acute lymphoblastic leukemia (ALL). Both DS-AMKL and the related transient myeloproliferative disorder (TMD) have GATA1 mutations as obligatory, early events. To identify mutations contributing to leukemogenesis in DS-ALL, we undertook sequencing of candidate genes, including FLT3, RAS, PTPN11, BRAF, and JAK2. Sequencing of the JAK2 pseudokinase domain identified a specific, acquired mutation, JAK2R683, in 12 (28%) of 42 DS-ALL cases. Functional studies of the common JAK2R683G mutation in murine Ba/F3 cells showed growth factor independence and constitutive activation of the JAK/STAT signaling pathway. High-resolution SNP array analysis of 9 DS-ALL cases identified additional submicroscopic deletions in key genes, including ETV6, CDKN2A, and PAX5. These results infer a complex molecular pathogenesis for DS-ALL leukemogenesis, with trisomy 21 as an initiating or first hit and with chromosome aneuploidy, gene deletions, and activating JAK2 mutations as complementary genetic events.


Asunto(s)
Síndrome de Down/genética , Janus Quinasa 2/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Animales , Secuencia de Bases , Análisis Mutacional de ADN , Síndrome de Down/complicaciones , Eliminación de Gen , Humanos , Ratones , Mutación , Reacción en Cadena de la Polimerasa , Polimorfismo de Nucleótido Simple
20.
Clin Transl Oncol ; 8(8): 560-5, 2006 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-16952844

RESUMEN

Childhood leukemia is a common pediatric cancer in the developed world, the disease is biologically diverse and there is much discussion as to its causal mechanisms. Acute lymphoblastic leukemia (ALL) is the most common subtype and infants with ALL have a greatly increased risk of treatment failure. There are molecular and biological properties of leukemic cells that determine treatment outcome; these can usually be attributed to distinct genetic abnormalities that alter the normal proliferative and survival signals of hematopoietic cells. Experimental evidence for the existence of leukemic stem cells (LSC) has been obtained, and it is presumed that these cells arise from mutations in normal hematopoetic stem cells or progenitor cells, and they are difficult to eradicate. LSC seem to be surprisingly different from their normal counterparts and therefore are obvious new targets for drug therapy. Therapeutic concepts using monoclonal antibodies have substantially improved response rates in patients with malignant lymphomas and are currently being evaluated in other types of cancer.


Asunto(s)
Leucemia/genética , Leucemia/terapia , Adolescente , Anticuerpos Monoclonales/uso terapéutico , Niño , Preescolar , Humanos , Inmunización Pasiva , Inmunoterapia Activa , Lactante , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Células Madre
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