Clonal heterogeneity of acute myeloid leukemia treated with the IDH2 inhibitor enasidenib

Nature Medicine
Lynn QuekParesh Vyas

Abstract

Mutations in the gene encoding isocitrate dehydrogenase 2 (IDH2) occur in several types of cancer, including acute myeloid leukemia (AML). In model systems, mutant IDH2 causes hematopoietic differentiation arrest. Enasidenib, a selective small-molecule inhibitor of mutant IDH2, produces a clinical response in 40% of treated patients with relapsed/refractory AML by promoting leukemic cell differentiation. Here, we studied the clonal basis of response and acquired resistance to enasidenib treatment. Using sequential patient samples, we determined the clonal structure of hematopoietic cell populations at different stages of differentiation. Before therapy, IDH2-mutant clones showed variable differentiation arrest. Enasidenib treatment promoted hematopoietic differentiation from either terminal or ancestral mutant clones; less frequently, treatment promoted differentiation of nonmutant cells. Analysis of paired diagnosis/relapse samples did not identify second-site mutations in IDH2 at relapse. Instead, relapse arose by clonal evolution or selection of terminal or ancestral clones, thus highlighting multiple bypass pathways that could potentially be targeted to restore differentiation arrest. These results show how mapping of clona...Continue Reading

References

Oct 29, 1997·Proceedings of the National Academy of Sciences of the United States of America·J E Arenas, J N Abelson
Feb 25, 2005·The New England Journal of Medicine·Susumu KobayashiBalázs Halmos
Dec 13, 2005·Gene·Olivier CordinPatrick Linder
Oct 29, 2010·The New England Journal of Medicine·Young Lim ChoiUNKNOWN ALK Lung Cancer Study Group
Oct 29, 2010·Genome Research·Gerton Lunter, Martin Goodson
Nov 9, 2010·Nature Methods·Yarden KatzChristopher B Burge
Feb 24, 2011·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Verena I GaidzikKonstanze Döhner
May 3, 2013·The New England Journal of Medicine·UNKNOWN Cancer Genome Atlas Research NetworkGreg Eley
May 10, 2013·The New England Journal of Medicine·Julia E MaxsonJeffrey W Tyner
Sep 24, 2013·Genome Research·Nicola E PotterMel Greaves
Jan 21, 2014·Cell Stem Cell·Lev M KatsPier Paolo Pandolfi
Feb 20, 2014·Proceedings of the National Academy of Sciences of the United States of America·M Ryan Corces-ZimmermanRavindra Majeti
May 30, 2014·The New England Journal of Medicine·Jennifer A WoyachJohn C Byrd
Dec 10, 2015·Leukemia·C C MasonM W Deininger
Jan 14, 2016·Nature·A Sorana MorrissyMichael D Taylor
Jun 9, 2016·The New England Journal of Medicine·Elli PapaemmanuilPeter J Campbell
Nov 1, 2016·Nature Genetics·Zachary J FaberJames R Downing
Jan 17, 2017·ELife·Marcel J TauchertRalf Ficner
Apr 27, 2017·The New England Journal of Medicine·Mariam Jamal-HanjaniUNKNOWN TRACERx Consortium
Apr 27, 2017·Nature·Christopher AbboshCharles Swanton
Jun 6, 2017·Acta Crystallographica. Section F, Structural Biology Communications·Karin MurakamiUmeharu Ohto
Jun 8, 2017·Blood·Eytan M SteinMartin S Tallman

❮ Previous
Next ❯

Citations

Sep 12, 2018·European Journal of Haematology·Sabine Kayser, Mark J Levis
Feb 5, 2019·Current Oncology Reports·Marco Cerrano, Raphael Itzykson
Dec 7, 2018·Hematology·Gregory W Roloff, Elizabeth A Griffiths
Jan 18, 2019·Leukemia & Lymphoma·Jan Philipp BewersdorfAmer M Zeidan
Aug 3, 2019·British Journal of Haematology·Peter HoklandMarie Bill
Nov 8, 2019·Blood·Katie A FennellMark A Dawson
Nov 7, 2019·International Journal of Cancer. Journal International Du Cancer·Anna P SokolenkoEvgeny N Imyanitov
Jan 3, 2020·Current Opinion in Oncology·Charlotte K Brierley, Adam J Mead
Jan 8, 2020·Nature Reviews. Cancer·David VetrieMhairi Copland
Dec 6, 2019·Oncogene·Alexandre Teixeira VessoniLuis Francisco Zirnberger Batista
Jun 4, 2020·International Journal of Molecular Sciences·Cristina PanuzzoDaniela Cilloni
Jul 27, 2018·Nature Reviews. Clinical Oncology·David Killock
Feb 16, 2019·Blood·Lars Bullinger
Mar 19, 2019·Frontiers in Genetics·Samantha L GoldmanChristopher E Mason
Oct 30, 2019·Biomarker Research·Xiaoyan Liu, Yuping Gong
Dec 7, 2019·Hematology·Guillaume Richard-Carpentier, Courtney D DiNardo
Jun 11, 2020·Blood·Susan DeWolf, Martin S Tallman
Jul 24, 2020·Oncology and Therapy·Alessandro FiorentiniAttilio Olivieri
Apr 26, 2019·International Journal of Molecular Sciences·Stephan R BohlFrank G Rücker
Nov 26, 2019·Blood·Courtney D DiNardo, Andrew H Wei
May 16, 2019·Cell Research·Xiao-Jian SunZhu Chen
Nov 15, 2018·Blood Advances·Gregory W Roloff, Elizabeth A Griffiths
Jun 6, 2019·International Journal of Molecular Sciences·Cristina PapayannidisAntonio Curti
Feb 6, 2020·Cold Spring Harbor Perspectives in Medicine·Cihangir DuyAri Melnick
Sep 22, 2020·Minerva medica·Maria Paola MartelliClaudio Cerchione
Feb 6, 2020·Cancer Discovery·Nicholas J ShortNaval Daver
Apr 18, 2019·Cancer Discovery·Caroline E McCoach, Trever G Bivona
Dec 3, 2020·Cancer Discovery·Ludovica Marando, Brian J P Huntly
Nov 17, 2019·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Ana Bela Sarmento-RibeiroIoannis P Trougakos
Feb 9, 2021·EMBO Molecular Medicine·Alexander C Lewis, Lev M Kats
Oct 16, 2020·Haematologica·Vikas Madan, H Phillip Koeffler
Oct 23, 2020·Nature Communications·Kiyomi MoritaKoichi Takahashi
Jan 12, 2021·Frontiers in Oncology·Vanessa E Kennedy, Catherine C Smith

❮ Previous
Next ❯

Datasets Mentioned

BETA
E-MTAB-6299
E-MTAB-6660

Methods Mentioned

BETA
flow-cytometry
genotyping
exome sequencing
RNA-seq
flow cytometry
DNA-seq
PCR
amplicon sequencing

Software Mentioned

STAR
ArrayExpress
GATK
Fluidigm Access Array
GraphPad Prism
Stampy
Mixture of Isoforms ( MISO
IGV
Unix

Related Concepts

Related Feeds

AML: Role of LSD1 by CRISPR (Keystone)

Find the latest rersearrch on the ability of CRISPR-Cas9 mutagenesis to profile the interactions between lysine-specific histone demethylase 1 (LSD1) and chemical inhibitors in the context of acute myeloid leukemia (AML) here.

Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a clinically and genetically heterogeneous disease with approximately 20,000 cases per year in the United States. AML also accounts for 15-20% of all childhood acute leukemias, while it is responsible for more than half of the leukemic deaths in these patients. Here is the latest research on this disease.

Blood And Marrow Transplantation

The use of hematopoietic stem cell transplantation or blood and marrow transplantation (bmt) is on the increase worldwide. BMT is used to replace damaged or destroyed bone marrow with healthy bone marrow stem cells. Here is the latest research on bone and marrow transplantation.