Dataset Information

Proteome analysis of AML cells upon CaSR-KO

ABSTRACT: Haematopoietic stem cells (HSC) reside in locations within the bone marrow microenvironment (BMM) featuring a slightly higher extracellular calcium ion concentration [eCa2+]. HSC respond to [eCa2+] via the G-protein coupled calcium-sensing receptor (CaSR), but the role of CaSR for leukaemia and leukaemia stem cells (LSC), the malignant counterpart to HSC, is poorly defined. Here we performed a proteomic analysis on Lin- MLL AF9+ cells, comparing WT cells to cells lacking CaSR using TMT-based proteomics.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Blood Cell, Bone Marrow

DISEASE(S): Acute Leukemia

SUBMITTER: Christian Münch

LAB HEAD: Daniela Krause

PROVIDER: PXD035937 | Pride | 2023-10-24

REPOSITORIES: Pride

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Publications

Distinct and targetable role of calcium-sensing receptor in leukaemia.

Pereira Raquel S RS Kumar Rahul R Cais Alessia A Paulini Lara L Kahler Alisa A Bravo Jimena J Minciacchi Valentina R VR Krack Theresa T Kowarz Eric E Zanetti Costanza C Godavarthy Parimala Sonika PS Hoeller Fabian F Llavona Pablo P Stark Tabea T Tascher Georg G Nowak Daniel D Meduri Eshwar E Huntly Brian J P BJP Münch Christian C Pampaloni Francesco F Marschalek Rolf R Krause Daniela S DS

Nature communications 20231006 1

Haematopoietic stem cells (HSC) reside in the bone marrow microenvironment (BMM), where they respond to extracellular calcium [eCa2+] via the G-protein coupled calcium-sensing receptor (CaSR). Here we show that a calcium gradient exists in this BMM, and that [eCa2+] and response to [eCa2+] differ between leukaemias. CaSR influences the location of MLL-AF9+ acute myeloid leukaemia (AML) cells within this niche and differentially impacts MLL-AF9+</s ...[more]

PMID: 37802982

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Project description:The branched-chain amino acid (BCAA) pathway and high levels of BCAA transaminase 1 (BCAT1) have recently been associated with aggressiveness in several cancer entities. However, the mechanistic role of BCAT1 in this process remains largely uncertain. Here, by performing high-resolution proteomic analysis of human acute myeloid leukaemia (AML) stem-cell and non-stem-cell populations, we find the BCAA pathway enriched and BCAT1 protein and transcripts overexpressed in leukaemia stem cells. We show that BCAT1, which transfers α-amino groups from BCAAs to α-ketoglutarate (αKG), is a critical regulator of intracellular αKG homeostasis. Further to its role in the tricarboxylic acid cycle, αKG is an essential cofactor for αKG-dependent dioxygenases such as Egl-9 family hypoxia inducible factor 1 (EGLN1) and the ten-eleven translocation (TET) family of DNA demethylases. Knockdown of BCAT1 in leukaemia cells caused accumulation of αKG, leading to EGLN1-mediated HIF1α protein degradation. This resulted in a growth and survival defect and abrogated leukaemia-initiating potential. By contrast, overexpression of BCAT1 in leukaemia cells decreased intracellular αKG levels and caused DNA hypermethylation through altered TET activity. AML with high levels of BCAT1 (BCAT1high) displayed a DNA hypermethylation phenotype similar to cases carrying a mutant isocitrate dehydrogenase (IDHmut), in which TET2 is inhibited by the oncometabolite 2-hydroxyglutarate11,12. High levels of BCAT1 strongly correlate with shorter overall survival in IDHWTTET2WT, but not IDHmut or TET2mutAML. Gene sets characteristic for IDHmut AML13 were enriched in samples from patients with an IDHWTTET2WTBCAT1high status. BCAT1highAML showed robust enrichment for leukaemia stem-cell signatures14,15, and paired sample analysis showed a significant increase in BCAT1 levels upon disease relapse. In summary, by limiting intracellular αKG, BCAT1 links BCAA catabolism to HIF1α stability and regulation of the epigenomic landscape, mimicking the effects of IDH mutations. Our results suggest the BCAA–BCAT1–αKG pathway as a therapeutic target to compromise leukaemia stem-cell function in patients with IDHWTTET2WT AML.

Dataset Information

Proteome analysis of AML cells upon CaSR-KO

Publications

Distinct and targetable role of calcium-sensing receptor in leukaemia.

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