Alternative splicing of hMLH1 in childhood acute lymphoblastic leukaemia and characterisation of the variably expressed Δ9/10 isoform as a dominant negative species

Peasland, Amy; Matheson, Elizabeth; Hall, Amy B.; Irving, Julie

doi:10.1016/j.leukres.2009.08.015

Cited by 7 publications

(6 citation statements)

References 21 publications

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“…In in vitro assays, both MLH1 p.Glu578_Glu632del (Δ16) and p.Glu633_Glu663del (Δ17) showed deficient interaction with PMS2 , as expected from the location of the deletions in the PMS2 binding domain . Additionally, MLH1 p.Glu227_Ser295del (Δ9/10) displayed deficient MMR function in an in vitro MMR assay , and a dominant negative effect in MMR‐proficient cell lines . The results of all these in vitro assays indicate that expression of MMR protein isoforms encoded by known alternative MMR transcripts can lead to defective MMR.…”

Section: Resultsmentioning

confidence: 99%

“…Many of the in‐frame coding alternative transcripts may also be ‘non‐functional’. It has been shown using in vitro analysis that expression of MLH1 protein isoforms carrying in‐frame deletions ( MLH1 Δ9/10, Δ16 and Δ17) can cause abrogated DNA repair function . However, it should be noted that not all in‐frame alternatively spliced transcripts will necessary cause loss of protein function.…”

Section: Discussionmentioning

confidence: 99%

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A review of mismatch repair gene transcripts: issues for interpretation of mRNA splicing assays

2014

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Many mismatch repair (MMR) gene disease-causing mutations identified in cancer patients result in aberrant messenger RNA (mRNA) splicing. However, mRNA assay interpretation can be complicated by the existence of naturally occurring alternative mRNA transcripts, most of which have not been formally described or fully characterized. Here, we provide a comprehensive catalogue of all MMR transcripts described to date, and a review of MMR nucleotide variants associated with an apparent upregulation of alternatively spliced transcripts. This work sets reference starting points for designing and interpreting MMR RNA analyses. Our database and literature searches retrieved 30 MLH1, 22 MSH2, 4 MSH6 and 9 PMS2 alternative transcripts, many predicted to introduce premature termination codons. Furthermore, we collected information on 66 MLH1, 24 MSH2 and 6 PMS2 nucleotide variants reported to be associated with altered expression of at least one of these alternative transcripts, and in many instances reported as splicing mutations. This review shows that there are many alternatively spliced MMR transcripts, which have potential to confound interpretation of splicing assays. These findings highlight the need to perform RNA analysis of patients systematically in parallel with control individuals, and call for the implementation of quantitative assessment of transcript levels for informed interpretation of mRNA assays.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A review of mismatch repair gene transcripts: issues for interpretation of mRNA splicing assays

2014

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“…The mutational spectrum in REH-resistant clones was similar to COSMIC signature 26 (cosine similarity .0.93), indicative of mismatch repair deficiency, consistent with reported MLH1 inactivation in REH cells. 57 The REH spectrum was dissimilar to novel signature B (cosine similarity ,0.3), likely due to the selection of resistant clones that may inactivate thiopurine-induced mutagenesis such as through drug efflux. 58 REH cells 59 and most other ALL cell lines were derived from relapsed leukemia [60][61][62] and are thus more likely to harbor drugresistant clones precluding thiopurine-induced mutagenesis, suggesting other experimental models may be preferable for testing whether thiopurines cause novel signature B.…”

Section: Experimental Identification Of Thiopurines As the Cause Of Novel Signature Bmentioning

confidence: 97%

Therapy-induced mutations drive the genomic landscape of relapsed acute lymphoblastic leukemia

Brady

et al. 2020

Blood

207

239

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“…23 The existence of hMLH1 delEx16, delEx17, and delEx10-11 transcripts and their potential relevance to diseases has been reported in previous studies. [24][25][26][27] However, hMLH1 delEx10 or delEx11 transcripts have not been reported. The cause of occurrence and pathogenic role of all these aberrant hMLH1 transcripts in GC have not been extensively assessed either.…”

Section: Discussionmentioning

confidence: 99%

Effect of histone modifications on hMLH1 alternative splicing in gastric cancer

Zhao

Shi

et al. 2017

Tumour Biol.

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hMLH1 is one of the mismatch genes closely related to the occurrence of gastric cancer. Epigenetic regulation may play more important roles than gene mutations in DNA damage repair genes to drive carcinogenesis. In this article, we discuss the role of epigenetic changes, especially histone modifications in the regulation of hMLH1 alternative splicing. Our results showed that hMLH1 delEx10, delEx11, delEx10-11, delEx16 and delEx17 transcripts were ubiquitous in sporadic Chinese gastric cancer patients and gastric cancer cell lines. Lower level of H4K16ac and H3ac was detected in hMLH1 exon 10-11 region in gastric cancer cell lines when compared with human gastric mucosal epithelial cell line GES-1. A significant decrease of hMLH1 delEx11 and delEx10-11 was observed in gastric cancer cell lines after trichostatin A treatment. H3K36me3 and H3K4me2 levels were lower in hMLH1 exon 10-11 and exon 16-17 regions in gastric cancer lines when compared with GES-1. Aberrant transcripts such as hMLH1 delEx11 and delEx10-11 were significantly higher in gastric cancer cell lines after small interfering RNA-mediated knockdown of SETD2 (the specific methyltransferase of H3K36). The hMLH1 delEx10 and delEx10-11 transcripts were increased after interference of SRSF2. Taken together, our study demonstrates that lower level of histone acetylation and specific histone methylation such as H3K36me3 correlate with aberrant transcripts in hMLH1 exon 10-11 region. SRSF2 may be involved in these specific exons skipping as well.

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Alternative splicing of hMLH1 in childhood acute lymphoblastic leukaemia and characterisation of the variably expressed Δ9/10 isoform as a dominant negative species

Cited by 7 publications

References 21 publications

A review of mismatch repair gene transcripts: issues for interpretation of mRNA splicing assays

A review of mismatch repair gene transcripts: issues for interpretation of mRNA splicing assays

Therapy-induced mutations drive the genomic landscape of relapsed acute lymphoblastic leukemia

Effect of histone modifications on hMLH1 alternative splicing in gastric cancer

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