Search

Your search keyword '"Marr HJ"' showing total 4 results
Start Over Author "Marr HJ"
4 results on '"Marr HJ"'

1. Genome-wide association study identifies susceptibility loci for acute myeloid leukemia

Author

Lin WY, Fordham SE, Hungate E, Sunter NJ, Elstob C, Xu Y, Park C, Quante A, Strauch K, Gieger C, Skol A, Rahman T, Sucheston-Campbell L, Wang J, Hahn T, Clay-Gilmour AI, Jones GL, Marr HJ, Jackson GH, Menne T, Collin M, Ivey A, Hills RK, Burnett AK, Russell NH, Fitzgibbon J, Larson RA, Le Beau MM, Stock W, Heidenreich O, Alharbi A, Allsup DJ, Houlston RS, Norden J, Dickinson AM, Douglas E, Lendrem C, Daly AK, Palm L, Piechocki K, Jeffries S, Bornhäuser M, Röllig C, Altmann H, Ruhnke L, Kunadt D, Wagenführ L, Cordell HJ, Darlay R, Andersen MK, Fontana MC, Martinelli G, Marconi G, Sanz MA, Cervera J, Gómez-Seguí I, Cluzeau T, Moreilhon C, Raynaud S, Sill H, Voso MT, Lo-Coco F, Dombret H, Cheok M, Preudhomme C, Gale RE, Linch D, Gaal-Wesinger J, Masszi A, Nowak D, Hofmann WK, Gilkes A, Porkka K, Milosevic Feenstra JD, Kralovics R, Grimwade D, Meggendorfer M, Haferlach T, Krizsán S, Bödör C, Stölzel F, Onel K, and Allan JM

Subjects
RISK, HLA, OLDER PATIENTS, AML, hemic and lymphatic diseases, HUMAN-LEUKOCYTE ANTIGEN, HIF-1-ALPHA, IMMUNE ESCAPE, CLONAL EVOLUTION, CANCER, GENE-MUTATIONS
Abstract

Acute myeloid leukemia (AML) is a hematological malignancy with an undefined heritable risk. Here we perform a meta-analysis of three genome-wide association studies, with replication in a fourth study, incorporating a total of 4018 AML cases and 10488 controls. We identify a genome-wide significant risk locus for AML at 11q13.2 (rs4930561; P = 2.15 × 10 -8 ; KMT5B). We also identify a genome-wide significant risk locus for the cytogenetically normal AML sub-group (N = 1287) at 6p21.32 (rs3916765; P = 1.51 × 10 -10 ; HLA). Our results inform on AML etiology and identify putative functional genes operating in histone methylation (KMT5B) and immune function (HLA).

Published
2021

2. Biallelic TET2 mutations confer sensitivity to 5'-azacitidine in acute myeloid leukemia.

Author

Stölzel F, Fordham SE, Nandana D, Lin WY, Blair H, Elstob C, Bell HL, Mohr B, Ruhnke L, Kunadt D, Dill C, Allsop D, Piddock R, Soura EN, Park C, Fadly M, Rahman T, Alharbi A, Wobus M, Altmann H, Röllig C, Wagenführ L, Jones GL, Menne T, Jackson GH, Marr HJ, Fitzgibbon J, Onel K, Meggendorfer M, Robinson A, Bziuk Z, Bowes E, Heidenreich O, Haferlach T, Villar S, Ariceta B, Diaz RA, Altschuler SJ, Wu LF, Prosper F, Montesinos P, Martinez-Lopez J, Bornhäuser M, and Allan JM

Subjects
Humans, Mice, Animals, Azacitidine, Kaplan-Meier Estimate, Mutation, DNA-Binding Proteins genetics, Leukemia, Myeloid, Acute genetics, Dioxygenases genetics
Abstract

Precision medicine can significantly improve outcomes for patients with cancer, but implementation requires comprehensive characterization of tumor cells to identify therapeutically exploitable vulnerabilities. Here, we describe somatic biallelic TET2 mutations in an elderly patient with acute myeloid leukemia (AML) that was chemoresistant to anthracycline and cytarabine but acutely sensitive to 5'-azacitidine (5'-Aza) hypomethylating monotherapy, resulting in long-term morphological remission. Given the role of TET2 as a regulator of genomic methylation, we hypothesized that mutant TET2 allele dosage affects response to 5'-Aza. Using an isogenic cell model system and an orthotopic mouse xenograft, we demonstrate that biallelic TET2 mutations confer sensitivity to 5'-Aza compared with cells with monoallelic mutations. Our data argue in favor of using hypomethylating agents for chemoresistant disease or as first-line therapy in patients with biallelic TET2-mutated AML and demonstrate the importance of considering mutant allele dosage in the implementation of precision medicine for patients with cancer.

Published
2023
Full Text
View/download PDF

3. Author Correction: Genome-wide association study identifies susceptibility loci for acute myeloid leukemia.

Author

Lin WY, Fordham SE, Hungate E, Sunter NJ, Elstob C, Xu Y, Park C, Quante A, Strauch K, Gieger C, Skol A, Rahman T, Sucheston-Campbell L, Wang J, Hahn T, Clay-Gilmour AI, Jones GL, Marr HJ, Jackson GH, Menne T, Collin M, Ivey A, Hills RK, Burnett AK, Russell NH, Fitzgibbon J, Larson RA, Le Beau MM, Stock W, Heidenreich O, Alharbi A, Allsup DJ, Houlston RS, Norden J, Dickinson AM, Douglas E, Lendrem C, Daly AK, Palm L, Piechocki K, Jeffries S, Bornhäuser M, Röllig C, Altmann H, Ruhnke L, Kunadt D, Wagenführ L, Cordell HJ, Darlay R, Andersen MK, Fontana MC, Martinelli G, Marconi G, Sanz MA, Cervera J, Gómez-Seguí I, Cluzeau T, Moreilhon C, Raynaud S, Sill H, Voso MT, Lo-Coco F, Dombret H, Cheok M, Preudhomme C, Gale RE, Linch D, Gaal-Wesinger J, Masszi A, Nowak D, Hofmann WK, Gilkes A, Porkka K, Milosevic Feenstra JD, Kralovics R, Grimwade D, Meggendorfer M, Haferlach T, Krizsán S, Bödör C, Stölzel F, Onel K, and Allan JM

Published
2022
Full Text
View/download PDF

4. Inhibition of ATR acutely sensitizes acute myeloid leukemia cells to nucleoside analogs that target ribonucleotide reductase.

Author

Fordham SE, Blair HJ, Elstob CJ, Plummer R, Drew Y, Curtin NJ, Heidenreich O, Pal D, Jamieson D, Park C, Pollard J, Fields S, Milne P, Jackson GH, Marr HJ, Menne T, Jones GL, and Allan JM

Subjects
Aged, Animals, Cell Line, Disease Models, Animal, Female, Humans, Leukemia, Myeloid, Acute metabolism, Mice, Middle Aged, Ataxia Telangiectasia Mutated Proteins antagonists & inhibitors, Leukemia, Myeloid, Acute genetics, Nucleosides metabolism, Ribonucleotide Reductases genetics
Abstract

The ataxia telangiectasia and Rad3-related (ATR) protein kinase promotes cancer cell survival by signaling stalled replication forks generated by replication stress, a common feature of many cancers including acute myeloid leukemia (AML). Here we show that the antileukemic activity of the chemotherapeutic nucleoside analogs hydroxyurea and gemcitabine was significantly potentiated by ATR inhibition via a mechanism involving ribonucleotide reductase (RNR) abrogation and inhibition of replication fork progression. When administered in combination with gemcitabine, an inhibitor of the M1 RNR subunit, the ATR inhibitor VX-970, eradicated disseminated leukemia in an orthotopic mouse model, eliciting long-term survival and effective cure. These data identify a synergistic interaction between ATR inhibition and RNR loss that will inform the deployment of small molecule inhibitors for the treatment of AML and other hematologic malignancies., (© 2018 by The American Society of Hematology.)

Published
2018
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results