Germ-line GATA2 p.THR354MET mutation in familial myelodysplastic syndrome with acquired monosomy 7 and ASXL1 mutation demonstrating rapid onset and poor survival

Bödör, Csaba; Renneville, Aline; Smith, Matthew; Charazac, Aurélie; Iqbal, Sameena; Étancelin, Pascaline; Cavenagh, Jamie; Barnett, Michael J.; Kramarzova, Karolina Skvarova; Krishnan, Biju; Matolcsy, András; Preudhomme, Claude; Fitzgibbon, Jude; Owen, Carolyn

doi:10.3324/haematol.2011.054361

Cited by 87 publications

(73 citation statements)

References 21 publications

(32 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The p.G646Wfs*12insG mutation was previously reported in two cousins with a GATA2 mutation who had developed MDS. 12 However, there has been concern over the validity of this particular mutation, with suggestions that it is a PCR artifact since it occurs immediately 3' to an eight base poly G sequence. 16 We confirmed this mutation by …”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, ASXL1 mutations were reported in two cousins with GATA2 mutations. 12 We, therefore, investigated whether ASXL1 mutations were a common "second hit" among GATA2 deficiency patients, and whether this correlated with leukemic transformation. ASXL1, the mammalian homolog of the Drosophila additional sex combs gene, is an essential component of two distinct chromatin-modifying complexes and is expressed in hematopoietic cell lineages.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Acquired ASXL1 mutations are common in patients with inherited GATA2 mutations and correlate with myeloid transformation

et al. 2013

View full text Add to dashboard Cite

© F e r r a t a S t o r t i F o u n d a t i o n (Online Supplementary Table S2). The PCR were done with AccuPrime Taq DNA Polymerase High Fidelity (Life Technologies, Grand Island, NY, USA) using the manufacturer's recommended conditions with 30 ng of substrate DNA and 35 amplification cycles, with the following amplification parameters: 94°C for 20 seconds; 58°C for 30 seconds, and 68°C for 60 seconds/kilobase of amplified product. The p.G646Wfs*12insG mutation was verified first by repeating the PCR using two different primer sets (Online Supplementary Table S1: primers 1/4, primers 2/3), then by repeating the reactions with different polymerase enzymes [AccuPrime Pfx (Life Technologies, Grand Island, NY, USA), DreamTaq (Thermo Scientific, Pittsburgh, PA, USA)] using the manufacturers' recommended conditions. PCR products were purified using the QIAquick PCR Purification Kit (QIAGEN Sciences, Germantown, MD, USA) and sequenced using ABI 3130XL and 3730 fluorescence-based sequencers. Sequences were analyzed with MacVector, version 12.0 (MacVector, Inc, Cary, NC, USA). Mutations were confirmed with independent PCR with separate primer sets. Statistical analyses were done with GraphPad Prism, version 5.0 (GraphPad Software, Inc., La Jolla CA, USA). The clinical protocols under which these studies were undertaken were reviewed and approved by the Institutional Review Board of the National Institutes of Health, Clinical Research Center. Patients in this study were enrolled in National Institutes of Health/National Institute of Allergy and Infectious Diseases ClinicalTrials.gov Identifier: NCT00018044, NCT00404560, NCT00001467, and National Cancer Institute ClinicalTrials.gov Identifier: NCT00923364. Results and DiscussionWe screened 48 patients with inherited GATA2 mutations to determine the incidence of somatic ASXL1 mutations. A schematic of the ASXL1 region that was sequenced, which contains ~90% of known ASXL1 mutations (COSMIC, v66 14 ), and the position of the mutations found in this study, are shown in Figure 1A. Sequence variations found in the Database of Single Nucleotide Polymorphisms (dbSNP) were not included as mutations Supplementary Table S3). Somatic ASXL1 mutations were detected in 14/48 (29%) patients with GATA2 deficiency (Table 1). All of these mutations were heterozygous and located within exon 13. The ASXL1 mutations found among GATA2 deficiency patients were similar to mutations previously reported in MDS and AML patients,15 including five independent cases of the most frequently described ASXL1 mutation (p.G646Wfs*12insG). The p.G646Wfs*12insG mutation was previously reported in two cousins with a GATA2 mutation who had developed MDS. 12 However, there has been concern over the validity of this particular mutation, with suggestions that it is a PCR artifact since it occurs immediately 3' to an eight base poly G sequence. 16 We confirmed this mutation by © F e r r a t a S t o r t i F o u n d a t i o nrepeating the PCR at least three times for each positive sample (for patie...

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Acquired ASXL1 mutations are common in patients with inherited GATA2 mutations and correlate with myeloid transformation

et al. 2013

View full text Add to dashboard Cite

show abstract

“…In all familial cases, the trait was inherited in an autosomal dominant fashion. A succession of follow-up reports established new cases and recalled a fascinating series of historical precedents by retrospective diagnosis (Kaur et al, 1972;Robinson et al, 1983;Biron et al, 1989;Ballas et al, 1990;Couderc et al, 1992;Horwitz et al, 1996;Wendland et al, 2000;Khanjari et al, 2003;Witzke et al, 2004;Bodor et al, 2012;Holme et al, 2012;Ishida et al, 2012;Kazenwadel et al, 2012;Camargo et al, 2013;Mace et al, 2013;Mutsaers et al, 2013;Niimi et al, 2013;Pasquet et al, 2013;Chou et al, 2014;Gao et al, 2014;West et al, 2014). The first we are aware of was a report in this journal in 1972, describing an Icelandic family with MDS/AML in association with trisomy 8 and PelgerHuet abnormality (Kaur et al, 1972), subsequently traced two generations later to a GATA2 T354M mutation (Dickinson et al, 2014).…”

Section: Clinical Syndromes Associated With Gata2 Mutationmentioning

confidence: 99%

“…Hereditary MDS/AML, rather than immune dysfunction, is the principle clinical feature of several kindreds with GATA2 mutation (Hahn et al, 2011;Bodor et al, 2012;Holme et al, 2012;Ishida et al, 2012;Fujiwara et al, 2014). MDS/AML is (Dickinson et al, 2014;Micol & Abdel-Wahab, 2014;Spinner et al, 2014).…”

Section: Acquired Genetic Abnormalities and Evolution To Leukaemiamentioning

confidence: 99%

Haematopoietic and immune defects associated with GATA2 mutation

Collin

2018

Pathology

View full text Add to dashboard Cite

SummaryHeterozygous familial or sporadic GATA2 mutations cause a multifaceted disorder, encompassing susceptibility to infection, pulmonary dysfunction, autoimmunity, lymphoedema and malignancy. Although often healthy in childhood, carriers of defective GATA2 alleles develop progressive loss of mononuclear cells (dendritic cells, monocytes, B and Natural Killer lymphocytes), elevated FLT3 ligand, and a 90% risk of clinical complications, including progression to myelodysplastic syndrome (MDS) by 60 years of age. Premature death may occur from childhood due to infection, pulmonary dysfunction, solid malignancy and MDS/acute myeloid leukaemia. GATA2 mutations include frameshifts, amino acid substitutions, insertions and deletions scattered throughout the gene but concentrated in the region encoding the two zinc finger domains. Mutations appear to cause haplo-insufficiency, which is known to impair haematopoietic stem cell survival in animal models. Management includes genetic counselling, prevention of infection, cancer surveillance, haematopoietic monitoring and, ultimately, stem cell transplantation upon the development of MDS or another lifethreatening complication.

show abstract

“…Second, recurrent loss-of-function ASXL1 mutations have been described in patients with GATA2 deficiency. However, the presence of ASXL1 mutations seems to be determined by the underlying karyotype, namely monosomy 7 [40]. This most frequent karyotype in pediatric is associated with ASXL1 and SETBP1 mutations, independently of germline GATA2 mutational status [34,41].…”

Section: Acquired Genetic Abnormalities In Carriers Of Germline Gata2mentioning

confidence: 99%

Heterogeneity of GATA2-related myeloid neoplasms

et al. 2017

View full text Add to dashboard Cite

Germ-line GATA2 p.THR354MET mutation in familial myelodysplastic syndrome with acquired monosomy 7 and ASXL1 mutation demonstrating rapid onset and poor survival

Abstract: ASXL1 mutations. We hypothesize that the nature of the secondary genetic events observed in GATA2-mutated individuals may explain the clinical heterogeneity observed within and between pedigrees.

Cited by 87 publications

References 21 publications

Acquired ASXL1 mutations are common in patients with inherited GATA2 mutations and correlate with myeloid transformation

Acquired ASXL1 mutations are common in patients with inherited GATA2 mutations and correlate with myeloid transformation

Haematopoietic and immune defects associated with GATA2 mutation

Heterogeneity of GATA2-related myeloid neoplasms

Contact Info

Product

Resources

About