Neural Stem Cell Marker Nestin As a Novel Unfavorable Prognostic Biomarker for Multiple Myeloma

Abstract Background:Neural stem cell marker nestin is a suitable diagnostic and prognostic indicator of malignancy and potential cancer stem cells marker in solid tumors. Currently, nestin has been demonstrated as an epithelial-to-mesenchymal transition related protein associated with tumor metastasis, chemoresistance, and metabolic changes through altering mitochondrial dynamics in solid tumors. However its role in hematological malignancies remains unknown. Our recent work confirmed nestin protein as a tumor-specific marker for CD138+38+ plasma cells (PC) of multiple myeloma (MM) and potential predictor of worse response to conventional and novel therapy but prognostic potential of nestin has never been studied in MM so far. Aim:The aim of this study was to evaluate whether pretreatment levels of nestin can predict overall (OS) and progression-free (PFS) survival of MM patients. Methods: Nestin was detected in CD138+38+PC of 84 newly diagnosed MM patients (36M/48F; median age 70 years) by flow cytometry. Nestin was assessed as the percentage of nestin-positive PC (Nes+PC) and ratio of median fluorescence intensity of nestin (MFI ratio) and isotypic control. Survival cut-off points were established based on time-dependent ROC analysis. P-values below 0.05 were considered as statistically significant in all analyses. Cox proportional hazards models were used to assess the association of prognostic factors with OS and PFS. The independence of the marker was assessed by multivariate Cox regression model. Survival rates were estimated using the Kaplan-Meier method. Differences in survival among subgroups of patients were compared using the log-rank test. Results: ROC analysis divided patients into 2 groups: high (>50) and low (≤50) %Nes+PC subgroup and high (>4) and low (≤4) MFI subgroup. High %Nes+PC subgroup were associated with shorter OS (p=0.042) and PFS (p=0.003). High MFI ratio subgroup (>4.4) were significantly associated with shorter OS (p=0.005); and PFS (p=0.025) (Fig.1). Univariate hazard ratios (HR) showed prognostic impact of %Nes+PC (p=0.003) and of MFI ratio (p=0.017) for OS; %Nes+PC (p=0.005) and of MFI ratio (p=0.028) for PFS (Tab.1). 5 parameters: ISS: stage 3 vs. stage 1, del p53, age (at diagnosis), M protein type: IgG vs. other, LDH (µkat/l) and Beta2 microglobulin (mg/l) were significantly associated with OS after adjustment by nestin. However %Nes+PC or MFI ratio did not achieve independent prognostic status in multivariable model (p=0.223 and p=0.989). Conclusion: These data demonstrate for the first time that nestin protein might have prognostic implication for MM. However, it does not appear to be independently associated with MM outcome when considering standard prognostic factors. The growing importance of nestin in key cell processes responsible for tumorigenesis and metastasis emphasizes the need for further investigation in MM. This pilot study requires to be further validated on a larger cohort of patients. Supported by NT14575, RVO-FNOs/2014/17P, IRP201550, SGS03/LF/2015-2016. Disclosures Besse: Mundipharma-EDO: Other: travel support. Hájek:Takeda: Consultancy; BMS: Honoraria; Janssen: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding.

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The Prognostic Impact of the Diagnostic CD34+/CD38- Cell Burden and Expression of the Stem Cell Marker GPR56 after Stem Cell Transplantation Depends on the AML Origin

Blood ◽

10.1182/blood-2019-127544 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 323-323

Author(s):

Madlen Jentzsch ◽

Marius Bill ◽

Juliane Grimm ◽

Dominic Brauer ◽

Julia Schulz ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Solid Tumors ◽

Cell Transplantation ◽

Research Funding ◽

De Novo ◽

Prognostic Impact ◽

Expression Levels ◽

Rheumatologic Diseases ◽

De Novo Aml

Introduction: Acute myeloid leukemia (AML) developing secondary after other hematologic diseases, or therapy related after cytotoxic treatment for solid tumors or rheumatologic diseases (s/tAML) is clinically, genetically & prognostically distinct from de novo diseases. Data indicate that s/tAML patients (pts) have inferior outcome compared to de novo cases after chemotherapy & therefore often require consolidation therapy using allogeneic stem cell transplantation (HSCT). Leukemic stem cells (LSC) initiate & maintain AML. They are also believed to exist within the CD34+/CD38- &/or high GPR56 expressing bone marrow (BM) population, which have been shown to impact adversely on outcome. The prognostic impact of LSC markers in de novovs s/tAML after HSCT with non-myeloablative conditioning intensity - where the therapeutic approach also relies on immunological graft-versus-leukemia effects - is unknown. Methods: We analyzed 379 AML pts who received an allogeneic peripheral blood HSCT in complete remission (CR, 82%) or CR with incomplete peripheral recovery (CRi, 18%) between 1999 & 2018 after non-myeloablative (3x30 mg/m2 Fludarabine & 2 Gy total body irradiation) conditioning. At diagnosis, cytogenetic & flow cytometric analyses were performed centrally. For pts with pre-treatment BM available the mutation status of CEBPA, NPM1 & presence of FLT3-ITD by fragment analyses as well as expression levels of GPR56 by qPCR were assessed. Using a next-generation targeted amplicon sequencing approach we analyzed a panel comprising 54 recurrently mutated (mut) genes in myeloid malignancies on the MiSeq platform (Illumina). Median follow up after HSCT was 3.7 years. Results: 229 pts (60%) had de novo & 150 pts (40%) had AML secondary to myelodysplastic syndrome (MDS, n=82), myeloproliferative neoplasm (MPN, n=22) or MDS/MPN (n=10), or therapy related after Non-Hodgkin lymphoma (n=9), solid tumors (n=25) or rheumatologic diseases (n=2). At diagnosis, s/tAML pts had lower white blood counts (P=.03), lower blasts in BM (P<.001) or blood (P=.007) & a higher BM CD34+/CD38- cell burden (P=.01) & GPR56 expression (P=.04). They also had worse European LeukemiaNet risk (P=.007), were less likely to have a normal karyotype by trend (P=.06), to have a core binding factor AML (P=.02), to be NPM1mut (P=.003), DNMT3Amut (P=.03) & to harbor a FLT3-ITD (P=.002) but more likely to be JAK2mut (P<.001). Comparing pts with s/tAML vsde novo AML, there was no significant different cumulative incidence of relapse (CIR, P=.85) or overall survival (OS, P=.29). Next, we evaluated the prognostic impact of the LSC-associated populations in pts with de novo or s/tAML separately. In pts with de novo AML, we observed a significantly higher CIR & shorter OS for pts harboring a high CD34+/CD38- cell burden (high vs low, 6% cut, P=.006 [Fig. 1A] & P=.003) & a higher CIR but not significantly different OS for pts with a low GPR56 expression (high vs low, median cut, P=.03 [Fig. 1B] & P=.95). Combining both parameters, we observed a stepwise higher CIR & shorter OS for pts with low expression of both variables vs pts with a low CD34+/CD38- cell burden but high GPR56 expression vs pts with a high CD34+/CD38-cell burden (P=.003 [Fig. 1C] & P=.05). In contrast, in pts with s/tAML, there was no prognostic significance of the CD34+/CD38- cell burden (CIR P=.38 [Fig. 1D] & OS P=.95), the GPR56 expression (CIR P=.64 [Fig. 1E] & OS P=.82) & both markers combined (CIR P=.57 [Fig. 1F] & OS P=.98). Also in multivariate analyses, the combination of both markers significantly impacted CIR (Hazard ratio 2.49, P<.001 after adjustment for donor type) & was the only significant factor for OS (Odds Ratio 0.68, P=.04) in de novo AML but not in s/tAML. Conclusion: While there was no significantly different CIR or OS in s/tAML compared to de novo AML pts undergoing non-myeloablative HSCT we observed a significant impact on outcome for the known LSC-associated prognosticators CD34+/CD38- cell burden & GPR56 expression levels at diagnosis only in de novo AML pts. Different underlying disease biology & possibly different LSC-associated populations may be relevant for disease reoccurrence in s/tAML. Figure Disclosures Jentzsch: Novartis: Honoraria; Jazz Pharmaceuticals: Honoraria. Niederwieser:Daichii: Speakers Bureau; Cellectis: Consultancy. Platzbecker:Abbvie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Schwind:Daiichi Sankyo: Honoraria; Novartis: Honoraria, Research Funding.

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Effects of irradiation on radioresistance, HOTAIR and epithelial-mesenchymal transition/cancer stem cell marker expression in esophageal squamous cell carcinoma

Oncology Letters ◽

10.3892/ol.2017.5774 ◽

2017 ◽

Vol 13 (4) ◽

pp. 2751-2757 ◽

Cited By ~ 5

Author(s):

Chunli Da ◽

Li Wu ◽

Yuting Liu ◽

Ruozheng Wang ◽

Ruiguang Li

Keyword(s):

Squamous Cell Carcinoma ◽

Stem Cell ◽

Esophageal Squamous Cell Carcinoma ◽

Cancer Stem Cell ◽

Epithelial Mesenchymal Transition ◽

Stem Cell Marker ◽

Cancer Stem Cell Marker ◽

Cell Marker ◽

Mesenchymal Transition ◽

Effects Of Irradiation On

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Stem cell marker nestin is expressed in plasma cells of multiple myeloma patients

Leukemia Research ◽

10.1016/j.leukres.2011.03.001 ◽

2011 ◽

Vol 35 (8) ◽

pp. 1008-1013 ◽

Cited By ~ 8

Author(s):

H. Svachova ◽

L. Pour ◽

J. Sana ◽

L. Kovarova ◽

K.R. Muthu Raja ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Plasma Cells ◽

Stem Cell Marker ◽

Cell Marker

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Predictive value for lymph node metastasis of epithelial-mesenchymal transition and cancer stem cell marker expression in early gastric cancer

Pathology - Research and Practice ◽

10.1016/j.prp.2017.03.010 ◽

2017 ◽

Vol 213 (9) ◽

pp. 1221-1226

Author(s):

Kyung Han Nam ◽

Hyuk Yoon ◽

Kyungbun Lee ◽

Do Joong Park ◽

Hyung-Ho Kim ◽

...

Keyword(s):

Gastric Cancer ◽

Stem Cell ◽

Lymph Node ◽

Lymph Node Metastasis ◽

Epithelial Mesenchymal Transition ◽

Stem Cell Marker ◽

Cancer Stem Cell Marker ◽

Cell Marker ◽

Mesenchymal Transition ◽

Node Metastasis

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Aspirin-mediated DKK-1 increase rescues Wnt-driven stem-like phenotype in human intestinal organoids

10.1101/809517 ◽

2019 ◽

Author(s):

Karen Dunbar ◽

Asta Valanciute ◽

Vidya Rajasekaran ◽

Thomas Jamieson ◽

Paz Freile Vinuela ◽

...

Keyword(s):

Stem Cell ◽

Epithelial Mesenchymal Transition ◽

Stem Cell Marker ◽

Cell Marker ◽

Mesenchymal Transition ◽

Intestinal Organoids ◽

Incidence And Mortality ◽

Stem Cell Populations ◽

Dickkopf 1 ◽

Human And Mouse

ABSTRACTAspirin reduces the incidence and mortality of colorectal cancer (CRC). Wnt signalling drives CRC development from initiation to progression through regulation of epithelial-mesenchymal transition (EMT) and cancer stem cell populations (CSC). Here, we investigated whether aspirin can rescue these pro-invasive phenotypes associated with CRC progression in Wnt-driven human and mouse intestinal organoids. Aspirin rescues the Wnt-driven cystic organoid phenotype by promoting budding in mouse and human Apc deficient organoids, which is paralleled by decreased stem cell marker expression. Aspirin-mediated Wnt inhibition in ApcMin/+ mice is associated with EMT inhibition and decreased cell migration, invasion and motility in CRC cell lines. Chemical Wnt activation induces EMT and stem-like alterations in CRC cells, which are rescued by aspirin. Aspirin increases expression of the Wnt antagonist Dickkopf-1 (DKK-1) in CRC cells and organoids derived from FAP patients. We provide evidence of phenotypic biomarkers of aspirin response with an increased epithelial and reduced stem-like state mediated by an increase in DKK-1. Thus we highlight a novel mechanism of aspirin-mediated Wnt inhibition and potential phenotypic and molecular biomarkers for trials.

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