![]() ![]() The only problem was, no one wanted to take the. The Author(s), under exclusive licence to Springer Nature Limited.īick AG, Weinstock JS, Nandakumar SK, Fulco CP, Bao EL, Zekavat SM, Szeto MD, Liao X, Leventhal MJ, Nasser J, Chang K, Laurie C, Burugula BB, Gibson CJ, Lin AE, Taub MA, Aguet F, Ardlie K, Mitchell BD, Barnes KC, Moscati A, Fornage M, Redline S, Psaty BM, Silverman EK, Weiss ST, Palmer ND, Vasan RS, Burchard EG, Kardia SLR, He J, Kaplan RC, Smith NL, Arnett DK, Schwartz DA, Correa A, de Andrade M, Guo X, Konkle BA, Custer B, Peralta JM, Gui H, Meyers DA, McGarvey ST, Chen IY, Shoemaker MB, Peyser PA, Broome JG, Gogarten SM, Wang FF, Wong Q, Montasser ME, Daya M, Kenny EE, North KE, Launer LJ, Cade BE, Bis JC, Cho MH, Lasky-Su J, Bowden DW, Cupples LA, Mak ACY, Becker LC, Smith JA, Kelly TN, Aslibekyan S, Heckbert SR, Tiwari HK, Yang IV, Heit JA, Lubitz SA, Johnsen JM, Curran JE, Wenzel SE, Weeks DE, Rao DC, Darbar D, Moon JY, Tracy RP, Buth EJ, Rafaels N, Loos RJF, Durda P, Liu Y, Hou L, Lee J, Kachroo P, Freedman BI, Levy D, Bielak LF, Hixson JE, Floyd JS, Whitsel EA, Ellinor PT, Irvin MR, Fingerlin TE, Raffield LM, Armasu SM, Wheeler MM, Sabino EC, Blangero J, Williams LK, Levy BD, Sheu WH, Roden DM, Boerwinkle E, Manson JE, Mathias RA, Desai P, Taylor KD, Johnson AD NHLBI Tran… See abstract for full author list ➔ Bick AG, et al. albert demeo obituaryAlbert V De Meo (1911-2013) - Find a Grave Memorial. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation. ![]() Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental knockdown of TCL1A expression. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but this effect was not seen in clones with driver mutations in DNMT3A. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. We applied this method to 5,071 people with clonal haematopoiesis. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. These lesions are precursors for blood cancers 2-6, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis 1. NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium Thomas W Blackwell ![]()
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