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Proteomic analysis of leukocytes upon Plekhm1-KO

ABSTRACT: Leukemia cells instruct their surrounding bone marrow microenvironment (BMM) rendering it hospitable to leukemia cell survival. Conversely, how cells of the BMM influence leukemia progression is less well understood. Pleckstrin homology domain family M member 1 (PLEKHM1) serves as a hub between fusion and secretion of intracellular vesicles. Here, we performed TMT-based quantitative proteomics to investigate the proteome of BMM-derived leucocytesfrom mice lacking Plekhm1 compared to wild-type animals, which have been transplanted withBCR-ABL1-expressing bone marrow cells.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Leukocyte, Bone Marrow

DISEASE(S): Acute Leukemia

SUBMITTER: Georg Tascher

LAB HEAD: Daniela Krause

PROVIDER: PXD027044 | Pride | 2023-01-16

REPOSITORIES: Pride

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Impact of mesenchymal stromal cell-derived vesicular cargo on B-cell acute lymphoblastic leukemia progression.

Karantanou Christina C Minciacchi Valentina R VR Kumar Rahul R Zanetti Costanza C Bravo Jimena J Pereira Raquel S RS Tascher Georg G Tertel Tobias T Covarrubias-Pinto Adriana A Bankov Katrin K Pfeffermann Lisa-Marie LM Bonig Halvard H Divieti-Pajevic Paola P McEwan David G DG Giebel Bernd B Münch Christian C Dikic Ivan I Krause Daniela S DS

Blood advances 20230401 7

Leukemia cells reciprocally interact with their surrounding bone marrow microenvironment (BMM), rendering it hospitable to leukemia cell survival, for instance through the release of small extracellular vesicles (sEVs). In contrast, we show here that BMM deficiency of pleckstrin homology domain family M member 1 (PLEKHM1), which serves as a hub between fusion and secretion of intracellular vesicles and is important for vesicular secretion in osteoclasts, accelerates murine BCR-ABL1+ B-cell acute ...[more]

PMID: 36044386

Similar Datasets

Proteomics of MSC-derived exosomes upon Plekhm1-KO

Project description:Leukemia cells instruct their surrounding bone marrow microenvironment (BMM) rendering it hospitable to leukemia cell survival. Conversely, how cells of the BMM influence leukemia progression is less well understood. Pleckstrin homology domain family M member 1 (PLEKHM1) serves as a hub between fusion and secretion of intracellular vesicles. Here, we performed label-free quantitative proteomics to investigate the exosomal cargo released by BMM-derived mesenchymal stromal cells (MSC) lacking Plekhm1 compared to wild-type cells.

2023-01-16 | PXD027041 | Pride

Proteome analysis of AML cells upon CaSR-KO

Project description: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.

2023-10-24 | PXD035937 | Pride

Characterization of mesenchymal stem cells in pre-B acute lymphoblastic leukemia

Project description:The way in which leukemia develops, progresses and responds to treatment is mediated largely by components of the bone marrow microenvironment (BMM). Increasing evidence shows that leukemic cells hijack the BMM, altering its functioning and establishing leukemia-supportive interactions with stromal and immune cells. While previous work has highlighted functional defects in the mesenchymal stem cell (MSC) population from the BMM of acute leukemias, a thorough characterization and molecular profiling of MSCs of pre-B cell acute lymphoblastic leukemia (B-ALL), the most common cancer in children, has not been conducted. Here, we investigated the transcriptome profiles of MSCs isolated from the BMM of an immunocompetent BCR-ABL1+ model of B-ALL.

2023-01-31 | GSE208719 | GEO

TIAR and FMRP shape pro-survival nascent proteome of leukemia cells in the bone marrow microenvironment

Project description:Chronic myeloid leukemia (CML) cells circulate between blood and bone marrow niche, representing different microenvironments. We studied the role of the two RNA binding proteins, T-cell-restricted intracellular antigen (TIAR) and the fragile X mental retardation protein (FMRP) in the regulation of protein translation in CML cells residing in settings mimicking peripheral blood microenvironment (PBM) and bone marrow microenvironment (BMM). We studied how conditions shaped the translation process through TIAR and FMRP activity, considering its relevance in therapy resistance. The QuaNCAT mass-spectrometric approach revealed that TIAR and FMRP have a discrete modulatory effect on protein synthesis and thus affect distinct aspects of leukemic cells functioning in the hypoxic niche. We demonstrate that TIAR substantially supports the resistance of CML cells to translation inhibition by homoharringtonine in the BMM. Overall, our results show that targeting post-transcriptional control should be considered when designing anti-leukemia therapeutic solutions.

2023-05-10 | PXD032332 | Pride

TBK1 p.E696K mutation causes autophagolysosomal dysfunction and ALS/FTD-like symptoms in mice

Project description:While deleterious mutations are responsible for the vast majority of TBK1-linked ALS/FTD cases, the ALS/FTD causing missense mutation p.E696K leads to a selective loss of TBK1/optineurin binding. Knock-in of this specific missense mutation causes progressive autophagolysosomal dysfunction and an ALS/FTD-like phenotype in mice, while, as opposed to TBK1 deletion, RIPK/TNF-α-dependent necroptosis or overt inflammation are absent. Our results highlight the role of autophagolysosomal dysfunction as a therapeutic target in TBK1-ALS/FTD.

2024-03-19 | PXD050731 | Pride

The cell-nonautonomous function of ID1 supports AML progression from the microenvironment via ANGPLT7

Project description:Bone marrow microenvironment (BMM) can maintain and regulate HSC and LSC via secreted components or direct interaction. Increasing evidence indicates that dissecting and targeting BMM-driven mechanisms of LSC might provide key adjuvant therapies to eradicate leukemia. ID1, a key transcriptional regulator in LSC previously identified by us, controls cytokine/chemokine production in the BMM, but the role of ID1 in AML-BMM remains obscure. Here, we report that ID1 is highly expressed in AML-BMM, especially in bone marrow mesenchymal stem cell (BMSC), and deletion of Id1 in BMM resulted in impaired AML progression in AML mouse model. Mechanistically, we found that Id1 deficiency markedly reduced the protein level of SP1 in mesenchymal cells co-cultured with AML cells. Through Id1-interactome analysis, we discovered Id1 interacts with Rnf4, the ubiquitin E3 ligase, and led to decreased Sp1 degradation. Disrupting ID1-RNF4 interaction by truncates in mesenchymal cells significantly decreased SP1 protein level and retarded the AML cell proliferation. We identified the target of Sp1, Angptl7, was the primary differentially expression protein factor in Id1-/- bone marrow supernatant fluid (BMSF) to regulate AML progression in mice. Taken together, our study highlights the critical role of ID1 in AML-BMM and assists development of diagnostic/therapeutic strategies for AML.

2023-10-04 | GSE219049 | GEO

Expression data of colony-stimulating factor (CSF) grown bone marrow derived cells

Project description:Granulocyte-Macrophage colony stimulating factor (GM-CSF) devlops heterogenous myeloid cell populations from bone marrow progenitor cells. In vitro generated bone marrow derived cells are excellent sources for obtaining dendritic cells or macrophages, but it is still not clear about the exact mixed population characteristics of GM-CSF grown cells. We revealed here that GM-CSF grown bone marrow cell derived attaching cells were composed of dendritic cells (GM-BMDC) as well as macrophages (GM-BMM). We compared the transcriptome profiles of these cell populations as well as M-CSF grown bone marrow derived macrophages (M-BMM). We used microarrays to detail the global profile of gene expressions between three populations of CSF-grown bone marrow derived cells: GM-CSF derived dendritic cells (GM-BMDC), GM-CSF derived macrophages (GM-BMM) and M-CSF derived macrophages (M-BMM).

2015-01-30 | GSE65425 | GEO

miRNA in mouse macrophages

Project description:By employing miRCURY LNAM-bM-^DM-" microRNA Array, we have identified a subset of 21 top miRNAs that are differentially expressed between GM-BMM and M-BMM cells To know the differential expression of miRNA in mouse GM-CSF-induced bone marrow-derived macrophages (GM-BMM) vs. M-CSF-induced BMM (M-BMM)

2013-04-17 | E-GEOD-46085 | biostudies-arrayexpress

Quantitative Proteome Responses to Oncolytic Reovirus in GM-CSF and M-CSF-Differentiated Bone Marrow-Derived Cells

Project description:To explore reovirus-macrophage interactions, we performed tandem mass tag (TMT)-based quantitative temporal proteomics on mouse bone marrow-derived macrophages (BMMs) generated with 2 cytokines, M-CSF and GM-CSF, representing anti- and pro-inflammatory macrophages, respectively. We quantified 6,863 proteins across five time points in duplicate, comparing M-CSF (M-BMM) and GM-CSF (GM-BMM) in response to OV. We find that GM-BMMs have lower expression of key intrinsic proteins that facilitate an anti-viral immune response, express higher levels of reovirus receptor protein JAM-A and are more susceptible to oncolytic reovirus infection compared to M-BMMs. Interestingly, although M-BMMs are less susceptible to reovirus infection and subsequent cell death, they initiate an anti-reovirus adaptive T cell immune response comparable to that of GM-BMMs. Taken together, these data describe distinct proteome differences between these two macrophage populations in terms of their ability to mount anti-viral immune responses.

2020-01-07 | PXD015203 | Pride

M-CSF-responsive immortal macrophages are a new model for studying macrophage function

Project description:We generated non-senescent, macrophage colony stimulating factor (M-CSF) dependent macrophages from murine fetal livers. These fetal liver macrophages (FLM-M) resemble bone marrow macrophage (BMM) morphology and express similar macrophage surface markers as BMM. In comparison to granulocyte monocyte-colony stimulating factor (GM-CSF) derived FLM (FLM-G), FLM-M have higher surface expression of CD11b, CD68, CD14 and CD64, and lower expression of CD11c. BMM, FLM-M and FLM-G all produce TNFα and IL-6 in response to lipopolysaccharide activation. BMM and FLM-M cells have similar phagocytic properties with 99.3% of BMM and FLM-M actively phagocytosing opsonized sheep erythrocytes and a phagocytic efficiency of 0.9. The average number of internalized erythrocytes per cell was higher (13.1±10.0) in BMM than in FLM-M (7.6±2.9). FLM-G had fewer actively phagocytic cells (86%), lower phagocytic efficiency (0.7) and fewer internalized erythrocytes per macrophage (4.2±2.1) than BMM or FLM-M. Principal component analysis and hierarchical clustering demonstrated mRNA expression profiles were more similar between BMM and FLM-M cells than FLM-G. Transcriptome comparison to the ImmGen tissue atlas shows cultured BMM and FLM-M cluster with macrophage progenitors and bone marrow macrophages. In conclusion, FLM-M cell cultures share major morphological, phenotypic and functional properties of BMM except for senescence, and can be an effective substitute to BMM. These new cells will facilitate study of macrophage biology by enabling experiments requiring long-term culture or genetic modifications.

2021-12-11 | GSE123647 | GEO

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