Microsatellite Instability (MSI) In High Risk Myelodysplastic Syndro…pair Genes: Indications for PARP Inhibitor Therapy.

| Blood Journal 10/05/2018, 09*34

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Microsatellite Instability (MSI) In High Risk Myelodysplastic Syndrome (MDS) and Acute Myeloid
Leukaemia (AML) Cells Promotes Frameshift Mutations In DNA Repair Genes: Indications for PARP
Inhibitor Therapy.
Terry J Gaymes, Azim Mohamedali, Austin G Kulasekararaj, Sydney Shall, and Ghulam J. Mufti

Blood 2010 116:1194;

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Abstract

Abstract 1194

Despite major advances in the biology and pathogenesis of myelodysplastic

syndrome (MDS) and acute myeloid leukaemia (AML) identification of the most
effective and safest form of treatment continue to present a formidable challenge
particularly in older patients. Older patients (>70 years) that constitute the majority
of MDS/AML patients are often resistant to chemotherapy, achieve short lived
remission and are not candidates for stem cell transplantation. Therefore the ○ Previous
emphasis is to prolong survival or improve the quality of life. Currently, a number of
Table of Contents
therapeutic strategies are being evaluated and these include treatment with DNA
Volume: 116
methyltransferase or histone deacetylase inhibitors. Seminal work in breast cancer
Issue: 21
have shown that inhibitors of poly ADP ribose polymerase (PARP) activity can Pages: 1194
selectively target tumour cells through exploitation of inherent DNA repair defects. DOI: https://doi.org/
MDS/AML are characterized by genomic instability (GI) and single nucleotide
polymorphism arrays (SNPA) karyotyping show that loss of heterozygosity (LOH) and
uniparental disomy (UPD) are common in MDS/AML and it has been suggested that
the underlying cause of this GI is a defect in double strand DNA repair. We have
demonstrated that non homologous end joining, a major pathway for the repair of
double strand DNA breaks is overactive and associated with extensive joining errors
in primary AML cells. Hence, potentially MDS/AML patients are candidates for PI
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therapy. We have also shown more recently, that 15% of MDS/AML primary patient
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cells and cell lines are sensitive to PARP inhibitors (PI) through exploitation of
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homologous recombination DNA repair defects. To further elucidate the % Cite This
mechanisms that underlie PI sensitivity in MDS/AML we tested for microsatellite
instability (MSI) in MDS/AML cell lines and high risk MDS patients and the presence
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of frameshift mutations in specific DNA repair genes that confer PI sensitivity. MSI is

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Microsatellite Instability (MSI) In High Risk Myelodysplastic Syndro…pair Genes: Indications for PARP Inhibitor Therapy. | Blood Journal 10/05/2018, 09*34

a change in length of a microsatellite allele caused by insertion or deletion of Jump to

nucleotides that are misincorporated during DNA replication and not removed by the .
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mismatch repair pathway. Using fluorescent PCR analysis, PI sensitive cell lines, P39, .
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KG-1 and Molm-13 showed MSI-high (instability at ≥ 2 loci) at 5 mononucleotide .
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microsatellites, in contrast to 12 PI insensitive cell lines that showed no MSI at these
loci. We also show using fluorescent PCR and DNA sequencing that these MSI
, Related Articles

positive cell lines demonstrate MSI (monoallelic 1–2 base pair [bp] deletion) in the
No related articles found.
coding region microsatellites of DNA repair genes, Ataxia telancgiectasia mutated
gene (ATM), CTiP, and MRE11. Monoallelic 1–2 bp base pair deletions at these loci
produced frameshift mutations that induced aberrant gene splicing transcripts in
ATM and MRE11 and a markedly truncated CTiP gene transcript. No MSI was
detected in DNA repair genes CHK1, RAD50, PTEN, BLM and ATR in these cell lines
and no mutations were observed at any DNA repair gene microsatellite in the 13 PI
insensitive cell lines. We then determined MSI in high risk MDS patients with or
without monosomy 7 (-7/del7q). 13 of 63 (21%) high risk MDS patients showed MSI
(9 MSI-low and 4 MSI-high). Of the 13 MSI positive patients, 7 (4 MSI-high, 3 MSI-
low) had monosomy 7 and other complex chromosomal abnormalities (Group 1,
54%), 2 (MSI-low) patients had isolated monosomy 7 (Group 2, 15%) whilst 4
patients (MSI-low) had normal cytogenetics (Group 3, 30%). Constitutional DNA from
these patients did not show MSI at these loci. Significantly, however, Group 3 with
MSI and normal cytogenetics all had widespread UPD and cryptic chromosome
changes determined by SNPA. Strikingly, thus all 13 patients with MSI possessed
chromosomal abnormalities, both gross and cryptic. Furthermore, 12 patients (19%)
found to be cytogenetically normal and lacking UPD and genomic aberrations by
SNPA did not show MSI. We have also identified that 3 patients with MSI-high (Group
1) and 1 patient with MSI-low (Group 3) had a monoallelic 1 bp deletion in the CTiP
exon coding microsatellite. 1 bp deletion within the coding exon of CTiP resulted in
an abbreviated CTiP gene transcript. In conclusion, we have made the important
correlation between MSI and subsequent frameshift mutations in specific DNA repair
genes with the gross and cryptic chromosomal changes observed in MDS/AML.
Identification of a cohort of MDS/AML patients with MSI would herald a significant
advancement for the selection of candidates for PI therapy.

Disclosures: No relevant conflicts of interest to declare.

© 2010 by The American Society of Hematology

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Microsatellite Instability (MSI) In High Risk Myelodysplastic Syndro…pair Genes: Indications for PARP Inhibitor Therapy. | Blood Journal 10/05/2018, 09*34

Robert Lowsky et al., Blood

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