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CML proteome analysis, QSTAR - Dual targeting of p53 and c-MYC selectively eliminates leukaemic stem cells

ABSTRACT: Using mass spectrometry the proteomesof CML were compared to normal tissue.

OTHER RELATED OMICS DATASETS IN: PRJNA112367PRJNA132313PRJNA208363PRJNA96045

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Cell, Blood

DISEASE(S): Chronic Myeloid Leukemia

SUBMITTER: Andrew Williamson

LAB HEAD: Prof. Anthony David Whetton

PROVIDER: PXD001503 | Pride | 2016-06-03

REPOSITORIES: Pride

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Dataset's files

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			Action	DRS
	022411_CML_Cyto_1-022411_CML_Cyto_01.mzXML	Mzxml
	022411_CML_Cyto_10.mzXML	Mzxml
	022411_CML_Cyto_11.mzXML	Mzxml
	022411_CML_Cyto_12.mzXML	Mzxml
	022411_CML_Cyto_13.mzXML	Mzxml

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Publications

Dual targeting of p53 and c-MYC selectively eliminates leukaemic stem cells.

Abraham Sheela A SA Hopcroft Lisa E M LE Carrick Emma E Drotar Mark E ME Dunn Karen K Williamson Andrew J K AJ Korfi Koorosh K Baquero Pablo P Park Laura E LE Scott Mary T MT Pellicano Francesca F Pierce Andrew A Copland Mhairi M Nourse Craig C Grimmond Sean M SM Vetrie David D Whetton Anthony D AD Holyoake Tessa L TL

Nature 20160608 7607

Chronic myeloid leukaemia (CML) arises after transformation of a haemopoietic stem cell (HSC) by the protein-tyrosine kinase BCR-ABL. Direct inhibition of BCR-ABL kinase has revolutionized disease management, but fails to eradicate leukaemic stem cells (LSCs), which maintain CML. LSCs are independent of BCR-ABL for survival, providing a rationale for identifying and targeting kinase-independent pathways. Here we show--using proteomics, transcriptomics and network analyses--that in human LSCs, ab ...[more]

PMID: 27281222

Similar Datasets

Dual targeting of p53 and c-MYC selectively eliminates leukaemic stem cells.

Project description:Chronic myeloid leukaemia (CML) arises after transformation of a haemopoietic stem cell (HSC) by the protein-tyrosine kinase BCR-ABL. Direct inhibition of BCR-ABL kinase has revolutionized disease management, but fails to eradicate leukaemic stem cells (LSCs), which maintain CML. LSCs are independent of BCR-ABL for survival, providing a rationale for identifying and targeting kinase-independent pathways. Here we show--using proteomics, transcriptomics and network analyses--that in human LSCs, aberrantly expressed proteins, in both imatinib-responder and non-responder patients, are modulated in concert with p53 (also known as TP53) and c-MYC regulation. Perturbation of both p53 and c-MYC, and not BCR-ABL itself, leads to synergistic cell kill, differentiation, and near elimination of transplantable human LSCs in mice, while sparing normal HSCs. This unbiased systems approach targeting connected nodes exemplifies a novel precision medicine strategy providing evidence that LSCs can be eradicated.

| S-EPMC4913876 | biostudies-literature

SCOPE 4 proteomics - Dual targeting of p53 and c-MYC selectively eliminates leukaemic stem cells

Project description:BaF3 were transfected with Jak2 V617F, Jak2 K539L or Mpl W515L, shotgun proteomic analysis with iTRAQ was performed

2016-05-26 | PXD002782 | Pride

Selective JAK2/ABL dual inhibition therapy effectively eliminates TKI-insensitive CML stem/progenitor cells.

Project description:Imatinib Mesylate (IM) and other tyrosine kinase inhibitor (TKI) therapies have had a major impact on the treatment of chronic myeloid leukemia (CML). However, TKI monotherapy is not curative, with relapse and persistence of leukemic stem cells (LSCs) remaining a challenge. We have recently identified an AHI-1-BCR-ABL-JAK2 protein complex that contributes to the transforming activity of BCR-ABL and IM-resistance in CML stem/progenitor cells. JAK2 thus emerges as an attractive target for improved therapies, but off-target effects of newly developed JAK2 inhibitors on normal hematopoietic cells remain a concern. We have examined the biological effects of a highly selective, orally bioavailable JAK2 inhibitor, BMS-911543, in combination with TKIs on CD34+ treatment-naïve IM-nonresponder cells. Combination therapy reduces JAK2/STAT5 and CRKL activities, induces apoptosis, inhibits proliferation and colony growth, and eliminates CML LSCs in vitro. Importantly, BMS-911543 selectively targets CML stem/progenitor cells while sparing healthy stem/progenitor cells. Oral BMS-911543 combined with the potent TKI dasatinib more effectively eliminates infiltrated leukemic cells in hematopoietic tissues than TKI monotherapy and enhances survival of leukemic mice. Dual targeting BCR-ABL and JAK2 activities in CML stem/progenitor cells may consequently lead to more effective disease eradication, especially in patients at high risk of TKI resistance and disease progression.

| S-EPMC4226710 | biostudies-literature

CML proteome analysis, TripleTOF 5600

Project description:Using mass spectrometry the proteomes of CML were compared to normal tissue.

2016-06-03 | PXD001504 | Pride

Targeting nucleoporin 214 selectively eliminates leukemia stem cells

Project description:To profile the E3 ligase associated with NUP214 neddylation, the NUP214 co-IP sample in THP-1 cells were examined by mass spectrometry.

2025-07-26 | PXD054462 | Pride

Targeting nucleoporin 214 selectively eliminates leukemia stem cells

Project description:To illustrate NUP214-interacting proteins, we performed co-immunoprecipitation (co-IP) followed by mass spectrometry using MLL-AF9-driven LSCs to characterize protein interactomes of NUP214.

2025-07-26 | PXD054438 | Pride

Targeting nucleoporin 214 selectively eliminates leukemia stem cells

Project description:LSCs from MLL-AF9-driven Nup214fl/fl and Nup214fl/fl,Tie2-Cre AML mice were sorted, followed by further proteomic assay.

2025-07-26 | PXD054471 | Pride

CML proteome analysis, LTQ Orbitrap Velos

Project description:Using mass spectrometry the proteomes of CML were compared to normal tissue.

2016-06-03 | PXD001502 | Pride

ANP32B-mediated repression of p53 contributes to maintenance of normal and CML stem cells

Project description:we demonstrate that conditional deletion of acidic leucine-rich nuclear phosphoprotein 32B (ANP32B) in hematopoietic cells impairs repopulation capacity and postinjury regeneration of HSCs. Mechanistically, ANP32B forms a repressive complex with and thus inhibits the transcriptional activity of p53 in hematopoietic cells, and p53 deletion rescues the functional defect in Anp32b-deficient HSCs. Of great interest, ANP32B is highly expressed in leukemic cells from patients with chronic myelogenous leukemia (CML). Anp32b deletion enhances p53 transcriptional activity to impair LSC function in a murine CML model and exhibits synergistic therapeutic effects with tyrosine kinase inhibitors in inhibiting CML propagation. In summary, our findings provide a novel strategy to enhance p53 activity in LSCs by inhibiting ANP32B and identify ANP32B as a potential therapeutic target in treating CML.

2021-09-27 | GSE184474 | GEO

A bispecific antibody targeting CD47 and CD20 selectively binds and eliminates dual antigen expressing lymphoma cells.

Project description:Agents that block the anti-phagocytic signal CD47 can synergize with pro-phagocytic anti-tumor antigen antibodies to potently eliminate tumors. While CD47 is overexpressed on cancer cells, its expression in many normal tissues may create an 'antigen sink' that could minimize the therapeutic efficacy of CD47 blocking agents. Here, we report development of bispecific antibodies (BsAbs) that co-target CD47 and CD20, a therapeutic target for non-Hodgkin lymphoma (NHL), that have reduced affinity for CD47 relative to the parental antibody, but retain strong binding to CD20. These characteristics facilitate selective binding of BsAbs to tumor cells, leading to phagocytosis. Treatment of human NHL-engrafted mice with BsAbs reduced lymphoma burden and extended survival while recapitulating the synergistic efficacy of anti-CD47 and anti-CD20 combination therapy. These findings serve as proof of principle for BsAb targeting of CD47 with tumor-associated antigens as a viable strategy to induce selective phagocytosis of tumor cells and recapitulate the synergy of combination antibody therapy. This approach may be broadly applied to cancer to add a CD47 blocking component to existing antibody therapies.

| S-EPMC4623422 | biostudies-literature

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