Targeting the spliceosome in chronic lymphocytic leukemia with the macrolides FD-895 and pladienolide-B

Kashyap, Manoj Kumar; Kumar, Deepak; Villa, Reymundo; Clair, James J. La; Benner, Chris; Šášik, Roman; Jones, Harrison; Ghia, Emanuela M.; Rassenti, Laura Z.; Kipps, Thomas J.; Burkart, Michael D.; Castro, Januario E.

doi:10.3324/haematol.2014.122069

Cited by 75 publications

(86 citation statements)

References 35 publications

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“…19,20 Dysregulation of splicing has been reported as an important factor in leukemia. [21][22][23] Alterations in spliceosome associated genes/proteins can significantly impact alternative splicing events like exon skipping or intron retention as reported in breast cancer, lung adenocarcinoma and chronic lymphocytic leukemia. 22,24,25 We identified dysregulation of multiple proteins encoded by genes involved in pre-mRNA splicing.…”

Section: Discussionmentioning

confidence: 99%

“…[21][22][23] Alterations in spliceosome associated genes/proteins can significantly impact alternative splicing events like exon skipping or intron retention as reported in breast cancer, lung adenocarcinoma and chronic lymphocytic leukemia. 22,24,25 We identified dysregulation of multiple proteins encoded by genes involved in pre-mRNA splicing. Overexpression ( 1.5 fold) of splicing regulators including SRSF5, SRSF6, SF3A2, SF3A3 and RBM17 was observed in HNSCC cells compared to a normal oral cell line.…”

Section: Discussionmentioning

confidence: 99%

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Dysregulation of splicing proteins in head and neck squamous cell carcinoma

Radhakrishnan

Nanjappa

Raja

et al. 2016

Cancer Biology & Therapy

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ABSRTRACTSignaling plays an important role in regulating all cellular pathways. Altered signaling is one of the hallmarks of cancers. Phosphoproteomics enables interrogation of kinase mediated signaling pathways in biological systems. In cancers, this approach can be utilized to identify aberrantly activated pathways that potentially drive proliferation and tumorigenesis. To identify signaling alterations in head and neck squamous cell carcinoma (HNSCC), we carried out proteomic and phosphoproteomic analysis of HNSCC cell lines using a combination of tandem mass tag (TMT) labeling approach and titanium dioxide-based enrichment. We identified 4,920 phosphosites corresponding to 2,212 proteins in six HNSCC cell lines compared to a normal oral cell line. Our data indicated significant enrichment of proteins associated with splicing. We observed hyperphosphorylation of SRSF protein kinase 2 (SRPK2) and its downstream substrates in HNSCC cell lines. SRPK2 is a splicing kinase, known to phosphorylate serine/arginine (SR) rich domain proteins and regulate splicing process in eukaryotes. Although genome-wide studies have reported the contribution of alternative splicing events of several genes in the progression of cancer, the involvement of splicing kinases in HNSCC is not known. In this study, we studied the role of SRPK2 in HNSCC. Inhibition of SRPK2 resulted in significant decrease in colony forming and invasive ability in a panel of HNSCC cell lines. Our results indicate that phosphorylation of SRPK2 plays a crucial role in the regulation of splicing process in HNSCC and that splicing kinases can be developed as a new class of therapeutic target in HNSCC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Dysregulation of splicing proteins in head and neck squamous cell carcinoma

Radhakrishnan

Nanjappa

Raja

et al. 2016

Cancer Biology & Therapy

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“…Analysis of splicing in CLL cells treated with pladienolide B identified an increase in intron retention and expression of pro-apoptotic isoforms of apoptosis-related genes. Importantly, this was only observed in CLL cells and not normal blood [72]. Unfortunately, first in man, clinical trials of E7107, a derivative of pladienolide B, in solid tumors were halted due to bilateral optic neuritis and gastrointestinal toxicity [71].…”

Section: Future Handling and Treatment Of Ddx41-associated Myeloid Mamentioning

confidence: 99%

Myeloid neoplasms with germline DDX41 mutation

et al. 2017

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to DDX41 mutation and highlights how each of these suggest potential therapeutic opportunities through the use of pathway-specific inhibitors.Keywords DDX41 · Myeloid malignancy · Myelodysplastic syndrome · Acute myeloid leukemia · Germline mutation · Predisposition Familial predisposition to myeloid neoplasmsMyeloid neoplasms are a heterogeneous group of diseases encompassing myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), all of which are characterized by abnormal growth and development of cells of the myeloid blood lineage. These disease groups can be further sub-categorized by a number of different morphological and molecular approaches which may correlate with responses to specific treatments [1]. AML and MDS Abstract Recently, DDX41 mutations have been identified both as germline and acquired somatic mutations in families with multiple cases of late-onset myelodysplastic syndrome (MDS) and/or acute myeloid leukemia. The majority of germline mutations are frameshift mutations suggesting loss of function with DDX41 acting as a tumor suppressor, and there is a common somatic missense mutation found in a majority of germline mutated tumors. Clinically, DDX41 mutations lead to development of high-risk MDS at an age similar to that observed in sporadic cohorts, presenting a unique challenge to hematologists in recognizing the familial context. Functionally, DDX41 has been shown to contribute to multiple pathways and processes including mRNA splicing, innate immunity and rRNA processing. Mutations in DDX41 result in aberrations to each of these in ways that could potentially impact on tumorigenesis-initiation, maintenance or progression. This review discusses the various molecular, clinical and biological aspects of myeloid malignancy predisposition due

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“…89 FD-895 caused induction of apoptosis in CLL cells in vitro (independent of SF3B1 genotype) at nanomolar concentrations, similar to PB. 90 A semisynthetic analog (17S-FD-895) with improved pharmacokinetic properties 91 administered to immunodeficient mice engrafted with primary human AML samples reduced their repopulating activity in secondary transplants and reverted the splicing signature in leukemia stems cells from "secondary AML-associated" to "healthy aging." 92 The genetic data from patients provided a priori support for the hypothesis that splicing factor mutant hematologic malignancies might be uniquely sensitive to splicing modulators.…”

Section: Splicing Modulatorsmentioning

confidence: 99%

Splicing factor gene mutations in hematologic malignancies

Sáez

Walter

Graubert

2017

Blood

112

108

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Alternative splicing generates a diversity of messenger RNA (mRNA) transcripts from a single mRNA precursor and contributes to the complexity of our proteome. Splicing is perturbed by a variety of mechanisms in cancer. Recurrent mutations in splicing factors have emerged as a hallmark of several hematologic malignancies. Splicing factor mutations tend to occur in the founding clone of myeloid cancers, and these mutations have recently been identified in blood cells from normal, healthy elderly individuals with clonal hematopoiesis who are at increased risk of subsequently developing a hematopoietic malignancy, suggesting that these mutations contribute to disease initiation. Splicing factor mutations change the pattern of splicing in primary patient and mouse hematopoietic cells and alter hematopoietic differentiation and maturation in animal models. Recent developments in this field are reviewed here, with an emphasis on the clinical consequences of splicing factor mutations, mechanistic insights from animal models, and implications for development of novel therapies targeting the precursor mRNA splicing pathway. (Blood. 2017;129(10):1260-1269 IntroductionThe control of messenger RNA (mRNA) processing is a crucial component of gene regulation. The precursor messenger RNA (premRNA) sequence contains exons that flank introns, which are removed during splicing.1 Human genes are remarkably complex, containing an average of 8 exons, with introns composing up to 90% of the pre-mRNA sequence.2,3 Up to 94% of human genes generate multiple mRNA isoforms. [4][5][6] The spliceosome is a multiprotein complex consisting of 5 small nuclear ribonucleoproteins (snRNPs) and more than 150 proteins that recognizes the elements near intron-exon boundaries and the branch site that catalyzes the excision of intronic regions. Additional trans-acting factors including SR proteins bind the cis-regulatory sequences (exonic and intronic silencers and enhancers) to promote or prevent spliceosome assembly. [7][8][9] The complexity of regulatory elements that control proper splicing makes this process not only critical to maintain tissue homeostasis, but also highly susceptible to hereditary and somatic mutations that are involved in disease. This review will discuss the implications of aberrant splicing on human disease, with a focus on the impact of somatic mutations in trans-acting splicing factors in hematologic malignancies. Splicing and diseaseA comprehensive analysis of The Cancer Genome Atlas (TCGA) project RNA sequencing (RNA-seq) data from 16 tumor types and matched normal tissue revealed evidence of global alternative splicing involving a variety of splicing junctions, including cassette exons, retrained introns, and competing 59 and 39 splice sites (SSs). 10 In particular, acute myeloid leukemia (AML) cells showed the largest number of alternative spliced events among tumor types.10 Recent evidence from analysis of paired DNA and RNA-seq data from TCGA has shown that somatic mutations affecting splicing regulatory sequences (sp...

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Targeting the spliceosome in chronic lymphocytic leukemia with the macrolides FD-895 and pladienolide-B

Cited by 75 publications

References 35 publications

Dysregulation of splicing proteins in head and neck squamous cell carcinoma

Dysregulation of splicing proteins in head and neck squamous cell carcinoma

Myeloid neoplasms with germline DDX41 mutation

Splicing factor gene mutations in hematologic malignancies

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