Grant Details
Grant Number: |
5R01CA284595-02 Interpret this number |
Primary Investigator: |
Eisfeld, Ann-Kathrin |
Organization: |
Ohio State University |
Project Title: |
Towards an Inclusive Genomic Risk Classification for Acute Myeloid Leukemia (AML) |
Fiscal Year: |
2024 |
Abstract
A. PROJECT SUMMARY
Acute myeloid leukemia (AML) is the most common adult acute leukemia. Molecular features such as
cytogenetics and somatic mutations are essential components of risk stratification; used in daily clinical
practice to determine treatment modality and intensity. Our knowledge of recurrent genetic AML-associated
features, survival associations, subsequent genetic risk classification and clinical practice is informed by large-
scale genomic studies performed over the past decade on patients of Central-European ancestry. Thus,
current clinical practice is predicated on the supposition that adequate testing has been performed, and that
genetic background should not affect the known AML-associated genetic and genomic landscape and genes
that associate with treatment response and/or that drive AML-genesis. However, our published and preliminary
data reveal that ancestry affects not only the frequencies and impact of known AML-associated gene
mutations, but also multiple recurrent variants in genes thus-far not implicated in AML-genesis. We
hypothesize that: a) known AML-associated drivers may carry different prognostic significance and might need
to be adjusted in clinical risk classifications depending on ancestry, and b) some unrecognized molecular
features are ancestry-associated drivers of AML-genesis and/or therapy resistance. We propose to extend our
initial studies of AML genomes and genomics to provide statistical confidence around frequently mutated
genes, and a more inclusive molecularly-adjusted risk and treatment stratification for AML patients. Next, we
will focus on NPM1c, a genotype which confers favorable outcome in AML patients with Central-European
ancestry, but poor outcomes in other ancestries. We will use cutting-edge single-cell multiomic assays to
delineate bystander clonal mutations from potential driver mutations, then we will biologically test their role in
clonality/leukemia-stem-cell frequency and treatment response. We expect to provide an inclusive
characterization of the genetic and genomic landscape of AML, identify those variants with prognostic
significance, and provide exemplars of here-to-fore unrecognized drivers of treatment response and survival.
The overall goal is to enable precision oncology approaches which accommodate the effects of underlying
human genetics.
Publications
Multiomic profiling identifies predictors of survival in African American patients with acute myeloid leukemia.
Authors: Stiff A.
, Fornerod M.
, Kain B.N.
, Nicolet D.
, Kelly B.J.
, Miller K.E.
, Mrózek K.
, Boateng I.
, Bollas A.
, Garfinkle E.A.R.
, et al.
.
Source: Nature genetics, 2024-10-04; , .
EPub date: 2024-10-04.
PMID: 39367245
Related Citations
White blood cell count levels are associated with inflammatory response and constitute independent outcome predictors in adult patients with acute myeloid leukemia aged <60 years.
Authors: Ozga M.
, Nicolet D.
, Mrózek K.
, Walker C.J.
, Blachly J.S.
, Kohlschmidt J.
, Orwick S.
, Carroll A.J.
, Larson R.A.
, Kolitz J.E.
, et al.
.
Source: American Journal Of Hematology, 2024-09-16 00:00:00.0; , .
EPub date: 2024-09-16 00:00:00.0.
PMID: 39283025
Related Citations
An immunophenotype-coupled transcriptomic atlas of human hematopoietic progenitors.
Authors: Zhang X.
, Song B.
, Carlino M.J.
, Li G.
, Ferchen K.
, Chen M.
, Thompson E.N.
, Kain B.N.
, Schnell D.
, Thakkar K.
, et al.
.
Source: Nature Immunology, 2024-03-21 00:00:00.0; , .
EPub date: 2024-03-21 00:00:00.0.
PMID: 38514887
Related Citations
Disparities in acute myeloid leukemia treatments and outcomes.
Authors: Eisfeld A.K.
.
Source: Current Opinion In Hematology, 2024-03-01 00:00:00.0; 31(2), p. 58-63.
EPub date: 2023-12-07 00:00:00.0.
PMID: 38059809
Related Citations