Dataset Information

Proteogenomic pathogenesis and classification of acute myeloid leukemia

ABSTRACT: Acute myeloid leukemia is a clinically and genetically heterogenous disease characterized by bone marrow infiltration with immature leukemic blasts that cause bone marrow failure. Patient age, comorbidities and genomic disease characteristics have a profound impact on patient outcome. Here, we present an integrated Multi-Omics analysis of protein and gene expression as well as cytogenetics and mutations to capture the rewiring of intracellular protein networks that is most likely caused by genomic aberrations. Because protein networks are downstream of genomic aberrations, we hypothesized that our Multi-Omics approach may add to the current AML classification by identifying proteomic AML subtypes with specific clinical and molecular features that could identify therapeutic vulnerabilities and aid in the identification of predictive biomarkers.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Cell, Leukocyte, Myeloid Cell, Bone Marrow, Blood

DISEASE(S): Acute Myeloid Leukemia,Acute Leukemia

SUBMITTER: Ashokkumar Jayavelu

LAB HEAD: Prof.Matthias Mann

PROVIDER: PXD023090 | Pride | 2022-03-08

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	H_Lang_300715_210815_AML_74_L1_1.raw	Raw
	H_Lang_300715_210815_AML_74_L1_10.raw	Raw
	H_Lang_300715_210815_AML_74_L1_11.raw	Raw
	H_Lang_300715_210815_AML_74_L1_13.raw	Raw
	H_Lang_300715_210815_AML_74_L1_14.raw	Raw

Items per page:

1 - 5 of 1774

Publications

The proteogenomic subtypes of acute myeloid leukemia.

Jayavelu Ashok Kumar AK Wolf Sebastian S Buettner Florian F Alexe Gabriela G Häupl Björn B Comoglio Federico F Schneider Constanze C Doebele Carmen C Fuhrmann Dominik C DC Wagner Sebastian S Donato Elisa E Andresen Carolin C Wilke Anne C AC Zindel Alena A Jahn Dominique D Splettstoesser Bianca B Plessmann Uwe U Münch Silvia S Abou-El-Ardat Khali K Makowka Philipp P Acker Fabian F Enssle Julius C JC Cremer Anjali A Schnütgen Frank F Kurrle Nina N Chapuy Björn B Löber Jens J Hartmann Sylvia S Wild Peter J PJ Wittig Ilka I Hübschmann Daniel D Kaderali Lars L Cox Jürgen J Brüne Bernhard B Röllig Christoph C Thiede Christian C Steffen Björn B Bornhäuser Martin M Trumpp Andreas A Urlaub Henning H Stegmaier Kimberly K Serve Hubert H Mann Matthias M Oellerich Thomas T

Cancer cell 20220303 3

Acute myeloid leukemia (AML) is an aggressive blood cancer with a poor prognosis. We report a comprehensive proteogenomic analysis of bone marrow biopsies from 252 uniformly treated AML patients to elucidate the molecular pathophysiology of AML in order to inform future diagnostic and therapeutic approaches. In addition to in-depth quantitative proteomics, our analysis includes cytogenetic profiling and DNA/RNA sequencing. We identify five proteomic AML subtypes, each reflecting specific biologi ...[more]

PMID: 35245447

Similar Datasets

Project description:Recurrent gene mutations, chromosomal translocations, acquired genomic copy number aberrations (aCNA) and copy-neutral loss-of-heterozygosity (cnLOH) underlie the genomic pathogenesis of acute myelogenous leukemia (AML). Genomic lesion types from all of these categories have been variously associated with AML patient outcome. However, the patterns of co-occurrence of such lesions are only now beginning to be defined, and we seek to further delineate the relative influence of different types of genomic alterations on clinical outcomes in AML. In this study, we performed SNP 6.0 array-based genomic profiling of aCNA/cnLOH along with sequence analysis of 13 recurrently mutated genes on purified leukemic blast DNA from 156 prospectively enrolled non-FAB-M3 AML patients across the clinical spectrum of de novo, secondary, and therapy-related AML. We identify positive and negative associations of gene mutations, specific aCNA/cnLOH or total aCNA/cnLOH counts with different AML types as well as the associations of specific mutations with overall genomic complexity or genomic stability. Further, we show that NPM1, RUNX1, ASXL1 and TP53 mutations, elevated SNP-A-based genomic complexity, and specific recurrent aCNAs predict response to induction chemotherapy. Finally, results of comprehensive multivariate analyses support a dominant role for TP53 mutations or elevated genomic complexity as predictors of short survival in AML. Integrated genomic profiling of a clinically relevant adult AML population reveals the interplay between gene mutations, recurrent aCNAs, and SNP-A-based genomic complexity and identifies among them the genomic characteristics most associated with types of response to intensive induction therapies and with shortened overall survival. This study is based on 156 patients with previously untreated AML for which paired tumor and normal samples were available. The patients were enrolled into this study at the University of Michigan Comprehensive Cancer Center. The study was approved by the University of Michigan Institutional Review Board (IRBMED #2004-1022) and written informed consent was obtained from all patients prior to enrollment. Genomic DNA was extracted from purified AML blasts and paired buccal cells. DNA thus obtained was hybridized to Affymetrix SNP 6.0 arrays.

Project description:The frequent occurrence of persistent or relapsed disease following induction chemotherapy in AML necessitates a better understanding of the clonal relationship of AML in various disease phases. In this study, we employed SNP 6.0 array-based genomic profiling of acquired copy number aberrations (aCNA) and copy neutral LOH (cnLOH) together with sequence analysis of recurrently mutated genes to characterize paired AML genomes. We analyzed 28 AML sample pairs from patients that achieved complete remission with chemotherapy and subsequently relapsed and 11 sample pairs from patients with persistent disease following induction chemotherapy. Through review of aCNA/cnLOH and gene mutation profiles in informative cases we demonstrate that relapsed AML invariably represents reemergence or evolution of a founder clone. Furthermore, all individual aCNA or cnLOH detected at presentation persisted at relapse indicating that this lesion type is proximally involved in AML evolution. Analysis of informative paired persistent AML disease samples uncovered cases with two coexisting dominant clones of which at least one was chemotherapy sensitive and one resistant, respectively. These data support the conclusion that incomplete eradication of AML founder clones rather than stochastic emergence of fully unrelated novel clones underlies AML relapse and persistence with direct implications for clinical AML research This study is based on 39 patients with AML for which either paired enrollment or relapse samples or persistent disease samples were available. The patients were enrolled into this study at the University of Michigan Comprehensive Cancer Center. The study was approved by the University of Michigan Institutional Review Board (IRBMED #2004-1022) and written informed consent was obtained from all patients prior to enrollment. Genomic DNA was extracted from purified AML blasts and paired buccal cells. DNA thus obtained was hybridized to Affymetrix SNP 6.0 arrays. Note: There is no normal sample available for MIAML015.