PXD032051

PXD032051 is an original dataset announced via ProteomeXchange.

Title	Proteomic and phosphoproteomic profiling reveals ACSS2 facilitating metabolic support in Acute Myeloid Leukemia
Description	Acute myeloid leukemia (AML) is a malignancy of transformed hematopoietic progenitors, which is curable in only 25-50% of patients thus the risk of relapse remains the major challenge. Considerable efforts in improving outcome through the understanding of AML biology elucidate that AML is not autonomous but rather supported by a complex multicellular-bone marrow microenvironment for leukemogenesis, leukemia expansion, and chemoresistance. Within the microenvironment, bone marrow mesenchymal stroma cells (BMSC) safeguard leukemia allowing rapid growth and enable resistance to therapy. Herein, we modeled leukemia-stroma interactions to unravel the reciprocal signaling processes regulating leukemic cell growth and survival. First, we conducted a proteomic analysis of primary AML samples (n=13) cocultured with non-malignant stroma cells by utilizing liquid chromatography mass spectrometry (LC-MS/MS) to understand how the stroma contributes to AML cellular signaling. In the analysis, 84 proteins were significantly affected including upregulation of rate-limiting metabolic enzymatic proteins NAMPT, FASN, and HK1 in AML-stroma cocultures relative to AML monoculture. Through an epigenetic drug screen, we modeled stroma mediated protection of leukemia and uncovered prominent drug resistance by histone deacytlase inhibitor (HDACi) treatment in cocultured leukemic cell lines and cocultured primary AML. We performed a quantitative phosphoproteomics analysis of AML-stroma interactions of leukemic KG1a cells in monoculture and in coculture with stroma (Hs5) treated with HDACi. We uncovered phosphorylation networks of stroma mediated protection enriched in pathways involved in AMP-activated signaling, glucose catabolic processes and EGF/EGFR signaling with the most potent changes in hyper-phosphorylation of acetyl-coenzyme A synthetase (ACSS2, S30) and of hypo-phosphorylation acetyl-coenzyme A carboxylase alpha, (ACACA, S80) both of which are involved in acetyl-CoA (acetyl-CoA) utilization for fatty acid synthesis pathway. Validating these findings, we found that ACSS2 substrate, acetate, contributed to leukemic proliferative growth and ACSS2 loss impacted leukemia metabolic fitness. In addition, we uncovered a novel subgroup of AML patients based on high expression of ACSS1 or ACSS2, which significantly correlated with inferior outcome. The differentially upregulated genes of this ACSS1/2-high subgroup revealed a metabolic gene signature related to mitochondrial processes suggesting the metabolic state of AML may aid in predicting outcome. Our findings elucidate phosphoproteome network of AML-stroma interactions whereby overriding stroma mediated protection, we conclude, requires intervening the metabolic support by ACSS2 in AML.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:44:25.101.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Guido Mastrobuoni
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Q Exactive HF; Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2022-03-03 12:23:24	ID requested
1	2024-06-11 03:17:13	announced
⏵ 2	2024-10-22 06:44:25	announced	2024-10-22: Updated project metadata.

10.1038/S41417-024-00785-5;

submitter keyword: AML, shotgun proteomics, phosphoproteomics

Stefan Kempa
contact affiliation	Quantitative proteomics and metabolomics Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association Hannoversche Str. 28, 10115 Berlin
contact email	stefan.kempa@mdc-berlin.de
lab head
Guido Mastrobuoni
contact affiliation	Berlin Institute for Medical Systems Biology at the Max Delbrueck Centrum for Molecular Medicine
contact email	guido.mastrobuoni@mdc-berlin.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD032051
     1. Label: PRIDE project
     2. Name: Proteomic and phosphoproteomic profiling reveals ACSS2 facilitating metabolic support in Acute Myeloid Leukemia