Marked genetic heterogeneity in familial myelodysplasia/acute myeloid leukaemia

Holme, Harriet; Hossain, Upal; Kirwan, Michael; Walne, Amanda J.; Vulliamy, Tom; Dokal, Inderjeet

doi:10.1111/j.1365-2141.2012.09136.x

Cited by 69 publications

(63 citation statements)

References 19 publications

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“…Many families who carry mutations in the GATA2, TERT, TERC, RUNX1 and CEBPA genes have been repeatedly identified (17)(18)(19)(20)(21)(22). In contrast, the FAMLF gene identified in the Fujian AML family (14) was expressed only in affected individuals but not in healthy controls, suggesting that this gene has a distinct pathophysiological role.…”

Section: Discussionmentioning

confidence: 99%

Protein expression and subcellular localization of familial acute myelogenous leukemia-related factor

Huang

Chen

et al. 2013

Oncology Reports

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Abstract. The present study was designed to evaluate the expression and subcellular distribution of the familial acute myelogenous leukemia-related factor (FAMLF). A 14-amino acid epitope of the predicted open reading frame of the FAMLF gene was identified using bioinformatics. This polypeptide was synthesized, conjugated to keyhole limpet hemocyanin and was subsequently used to produce antibodies. The antibody titer and specificity were characterized using ELISA and western blot assays, respectively. The antibody detected FAMLF protein expression in several human leukemia cell lines, bone marrow cells derived from one acute myeloid leukemia patient and one chronic myeloid leukemia patient, but not in bone marrow cells of healthy subjects. The FAMLF/ GFP fusion protein was expressed in both the nucleus and the cytoplasm of transfected NIH3T3 cells. Our results demonstrate that the FAMLF gene is expressed in an AML patient but not in healthy controls, suggesting its association with AML. IntroductionAcute myeloid leukemia (AML) is the most common hematological malignancy in adults, with a worldwide incidence of ~3.6 cases in 100,000 individuals (National Cancer Institute. SEER Stat Fact Sheets: Acute Myeloid Leukemia; http://seer. cancer.gov/statfacts/html/amyl.html). A number of AMLrelated chromosomal abnormalities and gene mutations have been identified, and their involvement in the regulation of DNA methylation, signal transduction, energy synthesis, and cellular structure has been reported (1).The identification of new AML-related genes may provide insight into disease prognosis, treatment response, and new therapeutic regimens for patients with AML. Mutations in CCAAT enhancer binding factor α (CEBPA) have been associated with prolonged recurrence-free survival in AML patients (2). Mutations in nucleophosmin-1 (NPM1) and the internal tandem duplications in FLT3 predict positive AML prognosis (3), and mutations in several genes such as MLL-PTD, FLT3/ITD, WT1, and C-KIT predict negative AML prognosis (4-7). Thus, screening for mutations in CEBPA, NPM1, FLT3, and KIT is part of the routine workup for AML (8,9).A number of drugs targeting AML-related genes have been tested for their efficacy in treating AML, including TNF-related apoptosis inducing ligand (TRAIL) and tipifarnib, an inhibitor of farnesyltransferase (FTase), alone or in combination with other anti-leukemia drugs (10,11). Inhibitors of histone deacetylase, proteasome and Bcl-2 antisense oligonucleotides have also been used as targeted drugs in the clinical treatment of AML (12). Furthermore, inhibitors of Fms-like tyrosine kinase 2 (FLT-2), such as lestaurtinib (CEP701), tandutinib (MLN518) and PKC412 have shown benefit in treating FLT3-associated AML (13).Previously, we identified a large family with a high incidence of AML in Fujian China (14). A total of 11 family members in 4 generations were diagnosed with AML; two patients developed acute erythroleukemia (M6), one suffered from minimally differentiated acute myeloblastic leukemia (M1), one ha...

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Section: Discussionmentioning

confidence: 99%

Protein expression and subcellular localization of familial acute myelogenous leukemia-related factor

Huang

Chen

et al. 2013

Oncology Reports

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“…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%

“…Initially, it was thought that point mutation of the second zinc finger, such as T354M, might confer an increased risk of leukaemic transformation over frameshift mutations or null alleles but this is not borne out by larger cohort studies (Dickinson et al, 2014;Spinner et al, 2014). Constitutive genetic background may have an influence on the risk of leukaemic transformation and susceptibility to infection although it is notable that a range of clinical phenotypes can be seen in different individuals within one pedigree (Holme et al, 2012;Mutsaers et al, 2013;Spinner et al, 2014). The acquisition of additional genetic abnormalities in the transformation of GATA2 mutation to multilineage dysplasia is clearly presaged by the high incidence of monosomy 7 and trisomy 8 in familial cases of MDS/AML (Hahn et al, 2011;Ostergaard et al, 2011;Bodor et al, 2012;West et al, 2013;Dickinson et al, 2014;Micol & Abdel-Wahab, 2014;Spinner et al, 2014).…”

Section: Acquired Genetic Abnormalities and Evolution To Leukaemiamentioning

confidence: 99%

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Haematopoietic and immune defects associated with GATA2 mutation

Collin

2018

Pathology

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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.

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“…4 However, familial AML is a genetically heterogeneous disorder, and the culprit genes in the majority of AML pedigrees remain obscure. 5 Moreover, accumulating experimental and epidemiological evidence suggests that no single mutation is sufficient to produce AML. 6 Thus, additional pedigrees are required to fully delineate the underlying mechanism of leukaemia.…”

Section: Introductionmentioning

confidence: 99%

Positional cloning and next-generation sequencing identified a TGM6 mutation in a large Chinese pedigree with acute myeloid leukaemia

et al. 2014

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An inherited predisposition to acute myeloid leukaemia (AML) is exceedingly rare, but the investigation of these families will aid in the delineation of the underlying mechanisms of the more common, sporadic cases. Three AML predisposition genes, RUNX1, CEBPA and GATA2, have been recognised, but the culprit genes in the majority of AML pedigrees remain obscure. We applied a combined strategy of linkage analysis and next-generation sequencing (NGS) technology in an autosomal-dominant AML Chinese family with 11 cases in four generations. A genome-wide linkage scan using a 500K SNP genotyping array was conducted to identify a previously unreported candidate region on 20p13 with a maximum multipoint heterogeneity LOD (HLOD) score of 3.56 (P ¼ 0.00005). Targeted NGS within this region and whole-exome sequencing (WES) revealed a missense mutation in TGM6 (RefSeq, NM_198994.2:c.1550T4G, p.(L517W)), which cosegregated with the phenotype in this family, and was absent in 530 healthy controls. The mutated amino acid was located in a highly conserved position, which may be deleterious and affect the activation of TGM6. Our results strongly support the candidacy of TGM6 as a novel familial AML-associated gene.

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Marked genetic heterogeneity in familial myelodysplasia/acute myeloid leukaemia

Cited by 69 publications

References 19 publications

Protein expression and subcellular localization of familial acute myelogenous leukemia-related factor

Protein expression and subcellular localization of familial acute myelogenous leukemia-related factor

Haematopoietic and immune defects associated with GATA2 mutation

Positional cloning and next-generation sequencing identified a TGM6 mutation in a large Chinese pedigree with acute myeloid leukaemia

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