Expression of a specific extracellular matrix signature is a favorable prognostic factor in acute myeloid leukemia

Izzi, Valerio; Lakkala, Juho; Devarajan, Raman; Savolainen, Eeva‐Riitta; Koistinen, Pirjo; Heljasvaara, Ritva; Pihlajaniemi, Taina

doi:10.1016/j.lrr.2017.12.001

Cited by 9 publications

(7 citation statements)

References 21 publications

(34 reference statements)

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“…Previous studies of ECM expression at the mRNA level have described a 15-ECM gene expression signature that is associated with survival for patients receiving intensive antileukemic treatment [ 33 , 34 , 35 ]. Ten of the proteins encoded by these 15 genes could be detected in our present proteomic studies ( Table S8 ), and five of them were not released at detectable levels by MSCs.…”

Section: Resultsmentioning

confidence: 99%

The Constitutive Extracellular Protein Release by Acute Myeloid Leukemia Cells—A Proteomic Study of Patient Heterogeneity and Its Modulation by Mesenchymal Stromal Cells

Aasebø

Brenner

Birkeland

et al. 2021

Cancers

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Extracellular protein release is important both for the formation of extracellular matrix and for communication between cells. We investigated the extracellular protein release by in vitro cultured normal mesenchymal stem cells (MSCs) and by primary human acute myeloid leukemia (AML) cells derived from 40 consecutive patients. We observed quantifiable levels of 3082 proteins in our study; for the MSCs, we detected 1446 proteins, whereas the number of released proteins for the AML cells showed wide variation between patients (average number 1699, range 557–2380). The proteins were derived from various cellular compartments (e.g., cell membrane, nucleus, and cytoplasms), several organelles (e.g., cytoskeleton, endoplasmatic reticulum, Golgi apparatus, and mitochondria) and had various functions (e.g., extracellular matrix and exosomal proteins, cytokines, soluble adhesion molecules, protein synthesis, post-transcriptional modulation, RNA binding, and ribonuclear proteins). Thus, AML patients were very heterogeneous both regarding the number of proteins and the nature of their extracellularly released proteins. The protein release profiles of MSCs and primary AML cells show a considerable overlap, but a minority of the proteins are released only or mainly by the MSC, including several extracellular matrix molecules. Taken together, our observations suggest that the protein profile of the extracellular bone marrow microenvironment differs between AML patients, these differences are mainly caused by the protein release by the leukemic cells but this leukemia-associated heterogeneity of the overall extracellular protein profile is modulated by the constitutive protein release by normal MSCs.

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Section: Resultsmentioning

confidence: 99%

The Constitutive Extracellular Protein Release by Acute Myeloid Leukemia Cells—A Proteomic Study of Patient Heterogeneity and Its Modulation by Mesenchymal Stromal Cells

Aasebø

Brenner

Birkeland

et al. 2021

Cancers

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“…Importantly, in a recent study, we evaluated the level of the expression of matrisome genes in 10,487 patients across 32 tumor types using TCGA data and demonstrated that matrisome gene expression can segregate different tumor types [ 31 ]. Last, “omic” technologies have uncovered ECM genes and proteins whose levels are predictive of cancer patient outcome [ 23 , 25 , 32 , 33 , 34 ]. However, while mutations in ECM genes have been linked to a plethora of diseases and syndromes [ 35 ], no study has focused on determining the presence and extent of genomic alterations and mutations in ECM genes in cancers, a crucial piece of information to further understanding of the tumor microenvironment (TME) [ 36 ].…”

Section: Introductionmentioning

confidence: 99%

Pan-Cancer Analysis of the Genomic Alterations and Mutations of the Matrisome

Izzi

Davis

Naba

2020

Cancers

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The extracellular matrix (ECM) is a master regulator of all cellular functions and a major component of the tumor microenvironment. We previously defined the “matrisome” as the ensemble of genes encoding ECM proteins and proteins modulating ECM structure or function. While compositional and biomechanical changes in the ECM regulate cancer progression, no study has investigated the genomic alterations of matrisome genes in cancers and their consequences. Here, mining The Cancer Genome Atlas (TCGA) data, we found that copy number alterations and mutations are frequent in matrisome genes, even more so than in the rest of the genome. We also found that these alterations are predicted to significantly impact gene expression and protein function. Moreover, we identified matrisome genes whose mutational burden is an independent predictor of survival. We propose that studying genomic alterations of matrisome genes will further our understanding of the roles of this compartment in cancer progression and will lead to the development of innovative therapeutic strategies targeting the ECM.

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“…About 21,380 new AML cases and 10,590 deaths from this disease were reported in 2017 by the American Cancer Society. 1 Despite the advancements in modern chemotherapy, the prognosis of patients with AML has remained poor. 2 , 3 Identifying the mechanisms involved in AML metastasis may lead to innovative treatment methods and improved patient outcomes.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of PDIA3 inhibits proliferation and invasion of human acute myeloid leukemia cells

Ye¹,

Fu²,

Dou³

et al. 2018

OTT

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IntroductionAcute myeloid leukemia (AML) is a common malignancy of the hematopoietic system. In bone marrow samples of AML patients, PDIA3 expression was higher than that in the samples of healthy controls. We aimed at exploring the effect of PDIA3 siRNA on proliferation, apoptosis, migration, and invasion of AML HL-60 and HEL cells.Materials and methodsRT-PCR was performed to identify PDIA3 expression. Cell proliferation was assessed by MTT. Flow cytometry analysis and transwell were used to detect cell apoptosis, migration and invasion. Gene set enrich-ment analysis (GSEA) was employed to explore the PDIA 3-associated pathways in AML. Western blotting was used for protein expression detection.ResultsPDIA3 siRNA significantly inhibited the proliferation of AML cells at 24 and 48 h. PDIA3 siRNA notably enhanced the percentage of apoptotic cells. The migration and invasion abilities of HL-60 and HEL cells in the PDIA3 siRNA group were significantly suppressed compared with those in the control and siNC groups. GSEA of the Cancer Genome Atlas dataset showed that Kyoto Encyclopedia of Genes and Genomes oxidative phosphorylation and amino sugar and nucleotide sugar metabolism pathways could be correlated with PDIA3 expression; this was further confirmed in AML cells by Western blotting. MAPK signaling was also blocked by PDIA3 siRNA.ConclusionPDIA3 siRNA effectively enhanced apoptosis, and suppressed proliferation, invasion, and migration of AML cells by regulating oxidative phosphorylation and amino sugar and nucleotide sugar metabolism pathways, and MAPK signaling, which can provide novel therapeutic targets for AML.

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Expression of a specific extracellular matrix signature is a favorable prognostic factor in acute myeloid leukemia

Cited by 9 publications

References 21 publications

The Constitutive Extracellular Protein Release by Acute Myeloid Leukemia Cells—A Proteomic Study of Patient Heterogeneity and Its Modulation by Mesenchymal Stromal Cells

The Constitutive Extracellular Protein Release by Acute Myeloid Leukemia Cells—A Proteomic Study of Patient Heterogeneity and Its Modulation by Mesenchymal Stromal Cells

Pan-Cancer Analysis of the Genomic Alterations and Mutations of the Matrisome

Downregulation of PDIA3 inhibits proliferation and invasion of human acute myeloid leukemia cells

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