RESUMEN
Studies on twins with concordant acute lymphoblastic leukemia (ALL) have revealed that ETV6-RUNX1 gene fusion is a common, prenatal genetic event with other driver aberrations occurring subclonally and probably postnatally. The fetal cell type that is transformed by ETV6-RUNX1 is not identified by such studies or by the analysis of early B-cell lineage phenotype of derived progeny. Ongoing, clonal immunoglobulin (IG) and cross-lineage T-cell receptor (TCR) gene rearrangements are features of B-cell precursor leukemia and commence at the pro-B-cell stage of normal B-cell lineage development. We reasoned that shared clonal rearrangements of IG or TCR genes by concordant ALL in twins would be informative about the fetal cell type in which clonal advantage is elicited by ETV6-RUNX1. Five pairs of twins were analyzed for all varieties of IG and TCR gene rearrangements. All pairs showed identical incomplete or complete variable-diversity-joining junctions coupled with substantial, subclonal and divergent rearrangements. This pattern was endorsed by single-cell genetic scrutiny in one twin pair. Our data suggest that the pre-leukemic initiating function of ETV6-RUNX1 fusion is associated with clonal expansion early in the fetal B-cell lineage.
Asunto(s)
Linfocitos B/patología , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Regulación Leucémica de la Expresión Génica , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Células Precursoras de Linfocitos B/patología , Linfocitos T/patología , Gemelos Monocigóticos/genética , Linfocitos B/metabolismo , Linaje de la Célula/genética , Células Clonales , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Femenino , Feto , Reordenamiento Génico de Linfocito T , Humanos , Masculino , Proteínas de Fusión Oncogénica/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Células Precursoras de Linfocitos B/metabolismo , Receptores Fc/genética , Receptores Fc/metabolismo , Linfocitos T/metabolismo , Factores de TiempoRESUMEN
Identical twins have provided unique insights on timing or sequence of genetic events in acute lymphoblastic leukaemia (ALL). To date, this has mainly focused on ALL with MLL or ETV6-RUNX1 fusions, with hyperdiploid ALL remaining less well characterised. We examined three pairs of monozygotic twins, two concordant and one discordant for hyperdiploid ALL, for single-nucleotide polymorphism (SNP)-defined copy number alterations (CNAs), IGH/L plus TCR gene rearrangements and mutations in NRAS, KRAS, FLT3 and PTPN11 genes. We performed whole exome sequencing in one concordant twin pair. Potential 'driver' CNAs were low, 0-3 per case, and all were different within a pair. One patient had an NRAS mutation that was lacking from leukaemic cells of the twin sibling. By exome sequencing, there were 12 nonsynonymous mutations found in one twin and 5 in the other, one of which in SCL44A2 was shared or identical. Concordant pairs had some identical IGH/L and TCR rearrangements. In the twin pair with discordant hyperdiploid ALL, the healthy co-twin had persistent low level hyperdiploid CD19+ cells that lacked a CNA present in the ALL cells of her sibling. From these data, we propose that hyperdiploid ALL arises in a pre-B cell in utero and mutational changes necessary for clinical ALL accumulate subclonally and postnatally.
Asunto(s)
Diploidia , Evolución Molecular , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Gemelos Monocigóticos , Cartilla de ADN , Exoma , Reordenamiento Génico de Linfocito T , Genes de Inmunoglobulinas , Humanos , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Pancreatitis is a well-recognized consequence of blood and marrow transplantation (BMT). In a 4-year period, between January 2001 and December 2004, five children who received a BMT in our institution were diagnosed as having pancreatitis. Four of these five children also had adenoviral infection. We report these four cases and highlight the importance of investigating for pancreatitis patients who have any abdominal symptoms post BMT, and include specific stool culture for viral isolation, if it is not already known.