Intronic splicing of hyaluronan synthase 1 (HAS1): a biologically relevant indicator of poor outcome in multiple myeloma

Adamia, Sophia; Reiman, Tony; Crainie, Mary; Mant, Michael J.; Belch, Andrew R.; Pilarski, Linda M.

doi:10.1182/blood-2004-10-3825

Cited by 58 publications

(79 citation statements)

References 40 publications

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“…Recent studies indicate that CD44 is functionally important in leukemia stem cells (Jin et al, 2006;Krause et al, 2006) and other studies point to a possible role for another hyaluronan-binding protein, Rhamm, in myeloma progenitors (Crainie et al, 1999;Maxwell et al, 2004). Hyaluronan appears to have a role in normal stem cell behavior (Avigdor et al, 2004;Matrosova et al, 2004;Nilsson et al, 2003;Pilarski et al, 1999) and hyaluronan synthases are altered in myeloma progenitors (Adamia et al, 2005;Calabro et al, 2002). Interestingly, another common marker for cancer stem-like cells is EpCAM, also known as ESA (Al-Hajj et al, 2003;Dalerba et al, 2007b;Li et al, 2007a).…”

Section: Regulation Of Cancer Stem Cell Properties By Hyaluronan and mentioning

confidence: 99%

Hyaluronan, CD44 and Emmprin: Partners in cancer cell chemoresistance

Toole

Slomiany

2008

Drug Resistance Updates

161

140

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Hyaluronan is not only an important structural component of extracellular matrices but also interacts with cells during dynamic cell processes such as occur in cancer. Consequently, interactions of hyaluronan with tumor cells play important cooperative roles in various aspects of malignancy. Hyaluronan binds to several cell surface receptors, including CD44, thus leading to co-regulation of signaling pathways that are important in regulation of multidrug resistance to anticancer drugs, in particular anti-apoptotic pathways induced by activation of receptor tyrosine kinases. Emmprin, a cell surface glycoprotein of the Ig superfamily, stimulates hyaluronan production and downstream signaling consequences. Emmprin and CD44 also interact with various multidrug transporters of the ABC family and monocarboxylate transporters associated with resistance to cancer therapies. Moreover, hyaluronan-CD44 interactions are critical to these properties in the highly malignant, chemotherapy-resistant cancer stem-like cells. Perturbations of the hyaluronan-CD44 interaction at the plasma membrane by various antagonists result in attenuation of receptor tyrosine kinase and transporter activities and inhibition of tumor progression in vivo. These antagonists, especially small hyaluronan oligomers, may be useful in therapeutic strategies aimed at preventing tumor refractoriness or recurrence due to drug-resistant sub-populations within malignant cancers.

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Section: Regulation Of Cancer Stem Cell Properties By Hyaluronan and mentioning

confidence: 99%

Hyaluronan, CD44 and Emmprin: Partners in cancer cell chemoresistance

Toole

Slomiany

2008

Drug Resistance Updates

161

140

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“…31 The NOTCH2 and FLT3 gene primer sequences are provided in supplemental Table 2. Obtained PCR products were detected using gel electrophoresis or capillary electrophoresis and DNA fragment analysis on the ABI31/30XL DNA genetic analyzer (Life Technologies).…”

Section: Methodsmentioning

confidence: 99%

“…TOPO-TA cloning and PCR reactions for sequencing were performed as described previously. 31 Positive colonies containing NOTCH2 and FLT3 plasmids were identified through testing individual bacterial colonies by colony PCR using gene-specific primer sets (supplemental Table 2). Sequencing was performed at the Dana-Farber Cancer Institute (DFCI)-Molecular Biology Laboratory facility on the ABI3730 DNA Genetic Analyzer.…”

Section: Methodsmentioning

confidence: 99%

“…Capillary electrophoresis and DNA fragment analyses were carried out as described previously. 31 Cloning and sequencing experiments cDNAs for cloning and sequencing were prepared from 1 mg RNA isolated from the blasts of 8 AML patients all expressing NOTCH2 and FLT3 splice variants. TOPO-TA cloning and PCR reactions for sequencing were performed as described previously.…”

Section: Methodsmentioning

confidence: 99%

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NOTCH2 and FLT3 gene mis-splicings are common events in patients with acute myeloid leukemia (AML): new potential targets in AML

Adamia

Bar-Natan

Haibe‐Kains

et al. 2014

Blood

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• Overall, our results suggest that NOTCH2 and FLT3 aberrant splicing is a common event in AML that correlates with disease status and may correlate with disease outcomes. • Selected variants of NOTCH2and FLT3 transcripts were detected in a significant number of AML patients and could be useful as disease markers.Our previous studies revealed an increase in alternative splicing of multiple RNAs in cells from patients with acute myeloid leukemia (AML) compared with CD34 1 bone marrow cells from normal donors. Aberrantly spliced genes included a number of oncogenes, tumor suppressor genes, and genes involved in regulation of apoptosis, cell cycle, and cell differentiation. Among the most commonly mis-spliced genes (>70% of AML patients) were 2, NOTCH2 and FLT3, that encode myeloid cell surface proteins. The splice variants of NOTCH2 and FLT3 resulted from complete or partial exon skipping and utilization of cryptic splice sites. Longitudinal analyses suggested that NOTCH2 and FLT3 aberrant splicing correlated with disease status. Correlation analyses between splice variants of these genes and clinical features of patients showed an association between NOTCH2-Va splice variant and overall survival of patients. Our results suggest that NOTCH2 and FLT3 mis-splicing is a common characteristic of AML and has the potential to generate transcripts encoding proteins with altered function. Thus, splice variants of these genes might provide disease markers and targets for novel therapeutics. (Blood. 2014;123(18):2816-2825

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“…This could be particularly meaningful in MM, where disease-specific alternate splicing events of several genes have been reported [76,77,78]. Moreover, RNA-seq is the technology of choice for the discovery and genome-wide expression analysis of non-coding RNAs, whose involvement in MM is increasingly documented and that are being investigated as a therapeutic target [79,80].…”

Section: Five-year Viewmentioning

confidence: 99%