Familial platelet disorder with propensity to acute myelogenous leukemia: Genetic heterogeneity and progression to leukemia via acquisition of clonal chromosome anomalies

Minelli, Antonella; Maserati, Emanuela; Rossi, Gabriele; Bernardo, Maria Ester; Stefano, Piero De; Cecchini, Maria Paola; Valli, Roberto; Albano, V.; Pierani, Paolo; Leszl, Anna; Sainati, Laura; Curto, Francesco Lo; Danesino, Cesare; Locatelli, Franco; Pasquali, Francesco

doi:10.1002/gcc.20030

Cited by 28 publications

(17 citation statements)

References 21 publications

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“…At least one family is reported with symptoms of FPD/AML without a RUNX1 mutation. 143 Stockley and colleagues described RUNX1 mutations in 3 families with a phenotype of reduced platelet densegranule secretion. 144 It is not clear whether these families represent a spectrum of FPD/AML phenotype or have a different inherited platelet disorder due to RUNX1 mutations.…”

Section: Familial Platelet Disorder With Predisposition To Acute Myelmentioning

confidence: 99%

Role of RUNX1 in hematological malignancies

Sood

Kamikubo

Liu

2017

Blood

363

319

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RUNX1 is a member of the core-binding factor family of transcription factors and is indispensable for the establishment of definitive hematopoiesis in vertebrates. RUNX1 is one of the most frequently mutated genes in a variety of hematological malignancies. Germ line mutations in RUNX1 cause familial platelet disorder with associated myeloid malignancies. Somatic mutations and chromosomal rearrangements involving RUNX1 are frequently observed in myelodysplastic syndrome and leukemias of myeloid and lymphoid lineages, that is, acute myeloid leukemia, acute lymphoblastic leukemia, and chronic myelomonocytic leukemia. More recent studies suggest that the wild-type RUNX1 is required for growth and survival of certain types of leukemia cells. The purpose of this review is to discuss the current status of our understanding about the role of RUNX1 in hematological malignancies.

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Section: Familial Platelet Disorder With Predisposition To Acute Myelmentioning

confidence: 99%

Role of RUNX1 in hematological malignancies

Sood

Kamikubo

Liu

2017

Blood

363

319

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“…Minelli et al postulated that the mutations seen in FPD cases have a mutation effect that induces additional genetic abnormalities and promotes progression to hematologic malignancies. 25 Marked associations between chromosome translocation and gene mutations have been reported: KIT mutation in core binding leukemia, t(8;21)/AML1-ETO and inv(16)(p13q22)/ CBF␤-MYH11, FLT3-ITD in leukemia with t(15;17)/PML-RAR␣, or with t(6;9)/DEK-CAN. We consider that it is important to find an association to administer clinically relevant treatment.…”

Section: Resultsmentioning

confidence: 99%

CBL mutation in chronic myelomonocytic leukemia secondary to familial platelet disorder with propensity to develop acute myeloid leukemia (FPD/AML)

Shiba

Hasegawa

Park

et al. 2012

Blood

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IntroductionFamilial platelet disorder with a propensity to develop acute myeloid leukemia (FPD/AML) is a rare autosomal dominant disease characterized by thrombocytopenia, abnormal platelet function, and a propensity to develop myelodysplastic syndrome (MDS) and AML. 1,2 Since Song et al reported haploinsufficiency of the RUNX1/CBFA2 gene, 3 more than 20 affected families have been reported. [4][5][6][7][8] Notably, various types of mono-allelic mutations of the RUNX1 gene have been found in patients with AML secondary to FPD. 3,7-9 RUNX1, which is a key regulator of definitive hematopoiesis and myeloid differentiation, is also commonly involved in sporadic cases of MDS and AML, by translocations in AML 10 and by point mutations in AML 11,12 and MDS. 13 Recently, a second RUNX1 alteration has been reported 8 ; however, no additional molecular abnormalities have been found so far.In this regard, recent reports of somatic mutations of the CBL proto-oncogene in myeloid neoplasms are intriguing because these CBL mutations have been shown to result in aberrant tyrosine kinase signaling, which would also lead to the activation of RAS signaling pathways. So far, we and others have reported that CBL mutations occurred in a variety of myeloid neoplasms, including de novo AML, 14,15 MDS,16,17 and myeloproliferative neoplasm, 16,17 especially in chronic myelomonocytic leukemia (CMML) 16,17 and juvenile myelomonocytic leukemia. 18 The importance of CBL mutations for leukemogenesis has substantially increased, which prompted us to search for possible CBL mutations in this pedigree.Here, we reported that CBL mutation developed at the time of diagnosis of CMML, but not during refractory cytopenia, in a Japanese patient with FPD/AML harboring a RUNX1 mutation. Methods RUNX1 mutation analysisDNA and RNA were extracted from peripheral blood (PB) of the proband, her sister, and their mother after obtaining informed consent. We performed mutation analysis of the RUNX1 gene by PCR followed by direct sequencing with the use of an ABI PRISM 310 Genetic Analyzer (Applied Biosystems). For further confirmation of deletion mutations, the PCR products were subcloned with the use of a TOPO TA Cloning Kit (Invitrogen) and then sequenced. Mutations were screened from exons 1-8 of the RUNX1 gene. CBL mutation analysisBecause CBL mutations thus far reported almost exclusively involved exons 8-9 that encode Linker/RING finger domains, we confined our mutation analysis to these exons, which were subjected to direct sequencing. Because the frequency of 11q-acquired uniparental disomy (11q-aUPD) was reported as ϳ 85%-90% in CBL mutations, we also analyzed the sample with Affymetrix GeneChip 250K NspI. [17][18][19] Genome-wide detection of copy number abnormalities or allelic imbalances was performed with CNAG/AsCNAR Version 3.0 software (http:// www.genome.umin.jp), which enabled sensitive detection of copy number neutral loss of heterozygosity (or aUPD). 19 In addition, we examined mutations of the following genes in the proband as previously rep...

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“…Deleterious mutations in the RUNX1 gene, located at 21q22, including missense, nonsense, frameshift mutations, and intragenic deletions, have been identified in the 19 of 20 families reported so far, [1][2][3][4][5][6][7] but considerable genotypic and phenotypic heterogeneity are observed. 8 No RUNX1 mutation was found in the remaining family, but exons 7 and 8 were not analyzed in this study. 6 Molecular analysis of leukemic cells from only 5 persons with FPD, 4 cases at AML stage 1,6 and 1 at myelodysplasia (MDS) stage, 6 has been performed to date, and no additional molecular abnormality, including second RUNX1 alteration, has been detected, raising the question of how haploinsufficiency of RUNX1 may contribute to the development of acute leukemia (AL).…”

Section: Introductionmentioning

confidence: 81%