A cellular hierarchy framework for understanding heterogeneity and predicting drug response in AML
Andy G.X. Zeng,Suraj Bansal,Liqing Jin,Amanda Mitchell,Weihsu Claire Chen,Hussein A. Abbas,Michelle Chan-Seng-Yue,Veronique Voisin,Peter van Galen,Anne Tierens,Meyling Cheok,Claude Preudhomme,Hervé Dombret,Naval Daver,P. Andrew Futreal,Mark D. Minden,James A. Kennedy,Jean C.Y. Wang,John E. Dick +18 more
TL;DR: The leukemia cell hierarchy make-up was determined from bulk transcriptomes of over 1000 patients through deconvolution using single-cell reference profiles of leukemia stem, progenitor, and mature cell types and converged into four overall classes, spanning Primitive, Mature, GMP, and Intermediate.
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Abstract: The treatment landscape of AML is evolving with promising therapies entering clinical translation, yet patient responses remain heterogeneous and biomarkers for tailoring treatment are lacking. To understand how disease heterogeneity links with therapy response, we determined the leukemia cell hierarchy make-up from bulk transcriptomes of over 1000 patients through deconvolution using single-cell reference profiles of leukemia stem, progenitor, and mature cell types. Leukemia hierarchy composition was associated with functional, genomic, and clinical properties and converged into four overall classes, spanning Primitive, Mature, GMP, and Intermediate. Critically, variation in hierarchy composition along the Primitive vs GMP or Primitive vs Mature axes were associated with response to chemotherapy or drug sensitivity profiles of targeted therapies, respectively. A 7-gene biomarker derived from the Primitive vs Mature axis was predictive of patient response to 105 investigational drugs. Thus, hierarchy composition constitutes a novel framework for understanding disease biology and advancing precision medicine in AML.
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Citations
Identification of the global miR-130a targetome reveals a role for TBL1XR1 in hematopoietic stem cell self-renewal and t(8;21) AML.
Gabriela Krivdova,Veronique Voisin,Erwin M. Schoof,Sajid A. Marhon,Alex Murison,Jessica McLeod,Martino Gabra,Andy G.X. Zeng,Stefan Aigner,Brian A. Yee,Alexander A. Shishkin,Eric L. Van Nostrand,Karin G. Hermans,Aaron Trotman-Grant,Nathan Mbong,James A. Kennedy,Olga I. Gan,Elvin Wagenblast,Daniel D. De Carvalho,Leonardo Salmena,Mark D. Minden,Gary D. Bader,Gene W. Yeo,John E. Dick,Eric R. Lechman +24 more
TL;DR: In this paper , the authors identify miR-130a as a regulator of HSC self-renewal and differentiation, and show that miR130a is highly expressed in acute myeloid leukemia (AML), where it is critical for maintaining the oncogenic molecular program mediated by the AML1-ETO complex.
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Clonal evolution in leukemia: preleukemia, evolutionary models, and clinical implications
20 Jul 2023
TL;DR: This review summarizes the current understanding of how genetic lesions define distinct clonal architectures and highlights two classical evolutionary models and their relevant prognostic implications.
High-expression of the innate-immune related gene UNC93B1 predicts inferior outcomes in acute myeloid leukemia
Qiaoli Li,Hong Pan,Zhenyuan Gao,Weiwang Li,Lele Zhang,Jingyu Zhao,Liwei Fang,Yajing Chu,Weiping Yuan,Jun Shi +9 more
TL;DR: Wang et al. as discussed by the authors extracted the RNA sequence data and clinical characteristics of acute myeloid leukemia (AML) from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression database (GTEx) to identify the key factors for prognosis.
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