Loss of RKIP is a frequent event in myeloid sarcoma and promotes leukemic tissue infiltration

Caraffini, Veronica; Perfler, Bianca; Berg, Johannes Lorenz; Uhl, Barbara; Schauer, Silvia; Kashofer, Karl; Ghaffari-Tabrizi-Wizsy, Nassim; Strobl, Herbert; Wölfler, Albert; Höefler, Gerald; Sill, Heinz; Zebisch, Armin

doi:10.1182/blood-2017-09-804906

Cited by 11 publications

(13 citation statements)

References 25 publications

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“…In a subtype of AML called myeloid sarcoma, leukemia cells can leave the blood system and form tumors in solid tissue by a process similar to extravasation and metastasis of solid cancers. Caraffini et al demonstrated that RKIP functions as a suppressor of this metastatic process [ 55 ]. Knocking down RKIP in AML cell lines resulted in more cells infiltrating the tissue and forming tumors in a chorioallantoic membrane assay, whereas RKIP over-expression showed the opposite effect.…”

Section: Mechanisms Of Rkip Downregulation and Strategies For Recomentioning

confidence: 99%

Targeting Raf Kinase Inhibitory Protein Regulation and Function

Yesilkanal

Rosner

2018

Cancers

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Raf Kinase Inhibitory Protein (RKIP) is a highly conserved kinase inhibitor that functions as a metastasis suppressor in a variety of cancers. Since RKIP can reprogram tumor cells to a non-metastatic state by rewiring kinase networks, elucidating the mechanism by which RKIP acts not only reveals molecular mechanisms that regulate metastasis, but also represents an opportunity to target these signaling networks therapeutically. Although RKIP is often lost during metastatic progression, the mechanism by which this occurs in tumor cells is complex and not well understood. In this review, we summarize our current understanding of RKIP regulation in tumors and consider experimental and computational strategies for recovering or mimicking its function by targeting mediators of metastasis.

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Section: Mechanisms Of Rkip Downregulation and Strategies For Recomentioning

confidence: 99%

Targeting Raf Kinase Inhibitory Protein Regulation and Function

Yesilkanal

Rosner

2018

Cancers

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“…Primary AML patient specimens were collected at the stage of diagnosis and the stage of relapse or primary chemorefractory disease (R/R stage) at the Division of Hematology, Medical University of Graz, Graz, Austria (MUG). All samples were processed by Ficoll density gradient centrifugation, and mononuclear cell fractions were stored in the Biobank at the MUG until further use as described previously [51][52][53][54][55][56]. Additionally, cytospin preparations from mononuclear cell layers were analyzed, and only samples with a blast cell percentage of >80% were retained for further analyses.…”

Section: Patient Samples and Cell Linesmentioning

confidence: 99%

“…All media were supplemented with 10% heat-inactivated FCS and 1× antibiotic-antimycotic, including 100 µg/mL streptomycin, 100 U/mL penicillin, and 0.25 µg/mL amphotericin B (Thermo Fisher Scientific, Waltham, MA, USA). Lentiviral transduction for overexpression of miR-23a-3p in THP-1 and U937 was performed using a psi-pEZX-MR03 expression construct (Genecopeia, Rockville, MD, USA) as previously described [28,51,53]. Stable selection and maintenance were performed in the presence of 1.0 µg/mL puromycin.…”

Section: Cell Culture Lentiviral Transduction and Transfectionmentioning

confidence: 99%

“…cDNA was synthesized from 1 µg RNA using the Taq Man®Reverse Transcription Reagents (Applied Biosystems, Foster City, CA, USA) for mRNA and miScript II Reverse Transcriptase Kit (Qiagen) for miRNA, respectively. Real-time quantitative PCR (qPCR) was performed using the ∆∆C t method, as previously described [51,53,[59][60][61][62]. B2M and GUSB were employed as control genes for mRNA analyses, whereas, RNU6 and SNORD44 were used for miRNA expression profiling.…”

Section: Qpcr and Immunoblot Analysismentioning

confidence: 99%

“…NB4 (for miRNA qPCR of the patient samples) and cells transfected with scrambled controls (for all other experiments), respectively, served as calibrators. Immunoblot was performed as described previously [51,53,59,61,62], using the following antibodies: Anti-TOP2B (#sc-365071; Santa Cruz, Dallas, TX, USA) and anti-β-Actin (#A5441; Sigma Aldrich, St. Louis, MO, USA).…”

Section: Qpcr and Immunoblot Analysismentioning

confidence: 99%

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Increased Expression of Micro-RNA-23a Mediates Chemoresistance to Cytarabine in Acute Myeloid Leukemia

Hatzl

Perfler

Wurm

et al. 2020

Cancers

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Resistance to chemotherapy is one of the primary obstacles in acute myeloid leukemia (AML) therapy. Micro-RNA-23a (miR-23a) is frequently deregulated in AML and has been linked to chemoresistance in solid cancers. We, therefore, studied its role in chemoresistance to cytarabine (AraC), which forms the backbone of all cytostatic AML treatments. Initially, we assessed AraC sensitivity in three AML cell lines following miR-23a overexpression/knockdown using MTT-cell viability and soft-agar colony-formation assays. Overexpression of miR-23a decreased the sensitivity to AraC, whereas its knockdown had the opposite effect. Analysis of clinical data revealed that high miR-23a expression correlated with relapsed/refractory (R/R) AML disease stages, the leukemic stem cell compartment, as well as with inferior overall survival (OS) and event-free survival (EFS) in AraC-treated patients. Mechanistically, we demonstrate that miR-23a targets and downregulates topoisomerase-2-beta (TOP2B), and that TOP2B knockdown mediates AraC chemoresistance as well. Likewise, low TOP2B expression also correlated with R/R-AML disease stages and inferior EFS/OS. In conclusion, we show that increased expression of miR-23a mediates chemoresistance to AraC in AML and that it correlates with an inferior outcome in AraC-treated AML patients. We further demonstrate that miR-23a causes the downregulation of TOP2B, which is likely to mediate its effects on AraC sensitivity.

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Special Clinical Scenarios: Extramedullary Disease

Stölzel

2021

Acute Myeloid Leukemia

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Loss of RKIP is a frequent event in myeloid sarcoma and promotes leukemic tissue infiltration

Cited by 11 publications

References 25 publications

Targeting Raf Kinase Inhibitory Protein Regulation and Function

Targeting Raf Kinase Inhibitory Protein Regulation and Function

Increased Expression of Micro-RNA-23a Mediates Chemoresistance to Cytarabine in Acute Myeloid Leukemia

Special Clinical Scenarios: Extramedullary Disease

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