An extracellular matrix signature in leukemia precursor cells and acute myeloid leukemia

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

doi:10.3324/haematol.2017.167304

Cited by 17 publications

(25 citation statements)

References 16 publications

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“…We found a core set of 80 ECM genes that were differentially regulated in leukemic cells with respect to their normal counterparts. 4 Notably, our results not only largely recapitulated previous non-systematic findings, but also gave them a wider context. Thus, in cells with high CD44 expression, we observed a significant upregulation of ECM proteins which would directly interact with CD44 itself, including structural substrates, such as collagen IV and XVIII and laminin beta 2 (COL4A5, COL18A1 and LAMB2, respectively), and proteinases implicated in ECM assembly, remodeling and growth factor activation, such as matrix metalloproteinase 2, ADAM metallopeptidase domain 17, bone morphogenetic protein 1 and cathepsin G (MMP2, ADAM17, BMP1 and CTSG, respectively).…”

supporting

confidence: 87%

“…When these two profiles were used to classify AML patients, we found that individuals with the "definitive leukemic" profile had much lower overall, diseasefree and event-free survival independently of karyotype aberrations or typical driver mutations, for example, in FLT3, NPM1 or IDH1 genes. 4 Recently, Foroushani et al provided another important confirmation of the view that AML actively creates its own ECM. They employed a sophisticated network analysis to identify the architecture of active gene regulatory networks in AML and found that the regulation of ECM modules is the most significant feature of AML transcriptional profile.…”

mentioning

confidence: 89%

“…In fact, we found that MMP9 belongs to a specific subnetwork of ECM elements interacting with CD44, and that the expression of CD44 characterizes patients with lower survival. 4 If we then consider that a previous report suggested that MMP9 levels correlate inversely with patients' risk of death, 14 we can easily envisage a regulatory mechanism that, in this CD44 subnetwork, transcribes genes that facilitate the spreading of AML while suppressing genes (such as MMP9) that would halt it.…”

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confidence: 99%

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Understanding the extracellular matrix in acute myeloid leukemia

2017

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confidence: 87%

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Understanding the extracellular matrix in acute myeloid leukemia

2017

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“…Further, cellular signaling via integrin and ECM binding has been described as playing important roles in AML progression, and hence, in overall disease prognosis [17][18][19][20]. However, the structural interactions that occur between integrins and the extracellular matrix to promote AML development have not been fully elucidated [21][22][23][24][25][26][27] This study investigated the role of integrin α7 (ITGA7) in AML cells, focusing on its interaction with the ECM. The results demonstrate that ITGA7 expression is a prognostic predictor for AML and suggest a novel mechanism for AML progression.…”

Section: Introductionmentioning

confidence: 99%

Integrin α7 and Extracellular Matrix Laminin 211 Interaction Promotes Proliferation of Acute Myeloid Leukemia Cells and Is Associated with Granulocytic Sarcoma

Kobayashi

Oda

Takizawa

et al. 2020

Cancers

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Acute myeloid leukemia (AML) with granulocytic sarcoma (GS) is characterized by poor prognosis; however, its underlying mechanism is unclear. Bone marrow samples from 64 AML patients (9 with GS and 55 without GS) together with AML cell lines PL21, THP1, HL60, Kasumi-1, and KG-1 were used to elucidate the pathology of AML with GS. RNA-Seq analyses were performed on samples from seven AML patients with or without GS. Gene set enrichment analyses revealed significantly upregulated candidates on the cell surface of the GS group. Expression of the adhesion integrin α7 (ITGA7) was significantly higher in the GS group, as seen by RT-qPCR (p = 0.00188) and immunohistochemistry of bone marrow formalin-fixed, paraffin-embedded (FFPE) specimens. Flow cytometry revealed enhanced proliferation of PL21 and THP1 cells containing surface ITGA7 in the presence of laminin 211 and stimulated ERK phosphorylation; this effect was abrogated following ITGA7 knockdown or ERK inhibition. Overall, high ITGA7 expression was associated with poor patient survival (p = 0.0477). In summary, ITGA7 is highly expressed in AML with GS, and its ligand (laminin 211) stimulates cell proliferation through ERK signaling. This is the first study demonstrating the role of integrin α7 and extracellular matrix interactions in AML cell proliferation and extramedullary disease development.

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“…CRISP3 is a member of the cysteine-rich secretory protein CRISP family with major role in female and male reproductive tract, and is mainly expressed in salivary gland and bone marrow 40 . Recently, 80 genes were reported as “extracellular matrix specific genes” in leukemia, and CRISP3 was among the downregulated DE genes reported 41 . CRISP3 associations with AML merit further investigation.…”

Section: Discussionmentioning

confidence: 99%

Stratified computational meta-analysis of 2213 acute myeloid leukemia patients reveals age- and sex-dependent gene expression signatures

Roushangar

Mias

2018

Preprint

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GM) 9 10In 2018 alone, an estimated 20,000 new acute myeloid leukemia (AML) patients 11 were diagnosed, in the United States, and over 10,000 of them are expected to 12 die from the disease. AML is primarily diagnosed among the elderly (median 68 13 years old at diagnosis). Prognoses have significantly improved for younger 14 patients, but in patients older than 60 years old as much as 70% of patients will 15 die within a year of diagnosis. In this study, we conducted stratified 16 computational meta-analysis of 2,213 acute myeloid leukemia patients compared 17 to 548 healthy individuals, using curated publicly available data. We carried out 18 analysis of variance of normalized batch corrected data, including considerations 19 for disease, age, tissue and sex. We identified 974 differentially expressed probe 20 sets and 4 significant pathways associated with AML. Additionally, we identified 21 70 sex-and 375 age-related probe set expression signatures relevant to AML. 22Finally, we used a machine learning model (KNN model) to classify AML patients 23 2 compared to healthy individuals with 90+% achieved accuracy. Overall our 24 findings provide a new reanalysis of public datasets, that enabled the 25 identification of potential new gene sets relevant to AML that can potentially be 26 used in future experiments and possible stratified disease diagnostics. 27 28 29 30 classification is highly dependent on the presence of chromosomal abnormalities, 47including chromosomal deletions, duplications, translocations, inversions, and 48 gene fusion. Mostly, AML is diagnosed through microscopic, cytogenetics, and 49 molecular genetic analyses of patients' blood and/or bone marrow samples. 50Microscopic examination is used to detect distinctive features (e.g. Auer rods) in 51 cell morphology, cytogenetic analysis to identify chromosomal structural 52 aberrations (e.g., t(8;21), inv(16), t(16;16), or t(9;11)), and molecular genetic 53 analysis to identify gene fusion (e.g., RUNX1-RUNX1T1 and CBFB-MYH11), and 54 mutations in genes frequently mutated in AML (e.g., NPM1, CEBPA, RUNX1, 55 FLT3) 6-8 . These cytogenetic and molecular genetic analyses are used to identify 56 prognosis markers that can be used to classify AML patients into three risk 57 categories: favorable, intermediate, and unfavorable. The largest group of AML 58 patients (almost 50%) however, present normal karyotype and lack genetic 59 abnormalities 7-10 . These patients are classified as intermediate risk, and often 60 have heterogeneous clinical outcome with standard therapy with risk of AML 61 relapse 11 . 62 63Additionally, AML prognosis worsens as age increases, and older patients 64 respond less to current treatments with poorer clinical outcomes than their 65 younger counterparts 12,13 . AML can occur in people of all ages but is primarily 66 diagnosed among the elderly (>60 years), with a median age of 68 year at 67 diagnosis 4 . Recent advances in AML biology expanded our understanding of its 68 complex genetic landscape and led to significant improv...

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An extracellular matrix signature in leukemia precursor cells and acute myeloid leukemia

Cited by 17 publications

References 16 publications

Understanding the extracellular matrix in acute myeloid leukemia

Understanding the extracellular matrix in acute myeloid leukemia

Integrin α7 and Extracellular Matrix Laminin 211 Interaction Promotes Proliferation of Acute Myeloid Leukemia Cells and Is Associated with Granulocytic Sarcoma

Stratified computational meta-analysis of 2213 acute myeloid leukemia patients reveals age- and sex-dependent gene expression signatures

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