METABOLIC REPROGRAMMING OF ACUTE MYELOID LEUKEMIA STEM- PROGENITOR CELLS AT RELAPSE
Author(s): ,
Martina Ghetti
Affiliations:
Istituto Scientifico Romagnolo per lo studio e la cura dei tumori IRST-IRCCS,Meldola,Italy
,
Antonella Padella
Affiliations:
Department of Experimental, Diagnostic and Specialty Medicine,'Seragnoli' institute of hematology University of Bologna,Bologna,Italy
,
Martina Pazzaglia
Affiliations:
Department of Experimental, Diagnostic and Specialty Medicine,'Seràgnoli' Institute of Hematology, University of Bologna,Bologna,Italy
,
Rossella De Tommaso
Affiliations:
Department of Experimental, Diagnostic and Specialty Medicine,'Seràgnoli' Institute of Hematology, University of Bologna,Bologna,Italy
,
Mariachiara Fontana
Affiliations:
Department of Experimental, Diagnostic and Specialty Medicine,'Seràgnoli' Institute of Hematology, University of Bologna,Bologna,Italy
,
Samantha Bruno
Affiliations:
Department of Experimental, Diagnostic and Specialty Medicine,'Seràgnoli' Institute of Hematology, University of Bologna,Bologna,Italy
,
Maria Teresa Bochicchio
Affiliations:
Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS,Meldola,Italy
,
Anna Ferrari
Affiliations:
Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS,Meldola,Italy
,
Roberta Napolitano
Affiliations:
Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS,Meldola,Italy
,
Eugenia Franchini
Affiliations:
Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS,Meldola,Italy
,
Jacopo Nanni
Affiliations:
Department of Experimental, Diagnostic and Specialty Medicine,'Seràgnoli' Institute of Hematology, University of Bologna,Bologna,Italy
,
Giovanni Marconi
Affiliations:
Department of Experimental, Diagnostic and Specialty Medicine,'Seràgnoli' Institute of Hematology, University of Bologna,Bologna,Italy
,
Cristina Papayannidis
Affiliations:
Department of Experimental, Diagnostic and Specialty Medicine,'Seràgnoli' Institute of Hematology, University of Bologna,Bologna,Italy
,
Daniel Remondini
Affiliations:
Department of Physics and Astronomy,University of Bologna,Bologna,Italy
,
Giovanni Martinelli
Affiliations:
Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS,Meldola,Italy
Giorgia Simonetti
Affiliations:
Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS,Meldola,Italy
EHA Library. Ghetti M. Jun 15, 2019; 267277; PS976
Dr. Martina Ghetti
Dr. Martina Ghetti
Contributions
Abstract

Abstract: PS976

Type: Poster Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 17:30 - 19:00

Location: Poster area

Background
Primary chemo-refractory disease and relapse are the most important causes of mortality in acute myeloid leukemia (AML) patients (Döhner et al., N. Engl. J. Med. 2015). Leukemia stem cells (LSCs) are likely responsible for disease relapse (Guzman et al., Blood 2007). Several genomic studies of newly-diagnosed and relapsed AML have revealed different patterns of clonal evolution, but little is known about metabolic dysregulations among these two groups. Metabolomics can identify endogenous cell metabolite biomarkers to be applied for monitoring disease progression, in order to develop new targeted therapies (D. Wang et al., Journal of Pharm and Biom Analysis 2019).

Aims
We aimed to identify relapse-specific metabolic alterations of CD34+ AML stem-progenitor cells. 

Methods
We analyzed metabolites using mass spectrometry (Metabolon) of CD34+ bone-marrow stem progenitor cells of 22 newly-diagnosed and 13 relapsed AML patients. To better address the relevance of the results, we also compared our samples with CD34+ cells from umbilical cord blood (21 donors). Statistically-significant differences in metabolite concentrations between the groups were evaluated by Welch’s t-test. KEGG and SMPDB annotation helped us in identifying the most relevant differences in terms of metabolic pathways.

Results
Mass spectrometry analysis identified differences in the concentration of 16 metabolites between newly-diagnosed and relapsed AML. In particular, we discovered different intermediates of lipid metabolism, as decreased 1-(1-enyl-palmitoyl)-2-palmitoyl-GPC (p= 0,0049), or involved in Kreb’s Cycle, like reduced fumarate (p=0,0393) in relapsed AML. Conversely, we observed a higher concentration of UDP-N-acetylglucosamine/galactosamine (p=0,0044), which is part of carbohydrate metabolism. Moreover, by comparing CD34+ cells from relapsed or newly-diagnosed AML with cord blood, we defined a set of metabolic features which may suggest metabolic adaptation of the post-chemotherapy AML clone. It is worth noting the decrease in uridine concentration (p=0,03), a metabolite of pyrimidine metabolism. Pyrimidine pathway is of great interest thanks to the development of new drugs as dihydroorotate dehydrogenase (DHODH) inhibitor, that reduces leukemic cell burden, decreases levels of leukemia-initiating cells (Sykes DB et al., Cell 2016). Of note, relapsed cells show reduced orotidine levels compared with cells from newly-diagnosed patients. Finally, KEGG and SMPDB annotation revealed enrichment for changes in compounds involved in Ketone Body Metabolism, Citric Acid Cycle and Mitochondrial Electron Transport Chain.

Conclusion
Our data are in line with a metabolic reprogramming of AML cells at relapse, including a shift from pyruvate oxidation to fatty acid β-oxidation, with altered mitochondrial oxidative phosphorylation in leukemia stem progenitor cells. The results suggest potential metabolic vulnerabilities of relapsed patients which could be exploited for novel targeted therapeutic strategies. Supported by EHA research fellowship award.

Session topic: 3. Acute myeloid leukemia - Biology & Translational Research

Keyword(s): Acute myeloid leukemia, Bone Marrow, CD34+ cells, Relapsed acute myeloid leukemia

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