Deletion of RUNX1 exons 1 and 2 associated with familial platelet disorder with propensity to acute myeloid leukemia

2018 ◽  
Vol 222-223 ◽  
pp. 32-37 ◽  
Author(s):  
Marcela Cavalcante de Andrade Silva ◽  
Ana Cristina Victorino Krepischi ◽  
Leslie Domenici Kulikowski ◽  
Evelin Aline Zanardo ◽  
Luciana Nardinelli ◽  
...  
Blood ◽  
2012 ◽  
Vol 120 (13) ◽  
pp. 2719-2722 ◽  
Author(s):  
Iléana Antony-Debré ◽  
Dominique Bluteau ◽  
Raphael Itzykson ◽  
Véronique Baccini ◽  
Aline Renneville ◽  
...  

Abstract RUNX1 gene alterations are associated with acquired and inherited hematologic malignancies that include familial platelet disorder/acute myeloid leukemia, primary or secondary acute myeloid leukemia, and chronic myelomonocytic leukemia. Recently, we reported that RUNX1-mediated silencing of nonmuscle myosin heavy chain IIB (MYH10) was required for megakaryocyte ploidization and maturation. Here we demonstrate that runx1 deletion in mice induces the persistence of MYH10 in platelets, and a similar persistence was observed in platelets of patients with constitutional (familial platelet disorder/acute myeloid leukemia) or acquired (chronic myelomonocytic leukemia) RUNX1 mutations. MYH10 was also detected in platelets of patients with the Paris-Trousseau syndrome, a thrombocytopenia related to the deletion of the transcription factor FLI1 that forms a complex with RUNX1 to regulate megakaryopoiesis, whereas MYH10 persistence was not observed in other inherited forms of thrombocytopenia. We propose MYH10 detection as a new and simple tool to identify inherited platelet disorders and myeloid neoplasms with abnormalities in RUNX1 and its associated proteins.


Blood ◽  
2012 ◽  
Vol 119 (11) ◽  
pp. 2612-2614 ◽  
Author(s):  
Norio Shiba ◽  
Daisuke Hasegawa ◽  
Myoung-ja Park ◽  
Chisato Murata ◽  
Aiko Sato-Otsubo ◽  
...  

Abstract Familial 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. So far, > 20 affected families have been reported. Recently, a second RUNX1 alteration has been reported; however, no additional molecular abnormalities have been found so far. We identified an acquired CBL mutation and 11q-acquired uniparental disomy (11q-aUPD) in a patient with chronic myelomonocytic leukemia (CMML) secondary to FPD with RUNX1 mutation but not in the same patient during refractory cytopenia. This finding suggests that alterations of the CBL gene and RUNX1 gene may cooperate in the pathogenesis of CMML in patients with FPD/AML. The presence of CBL mutations and 11q-aUPD was an important “second hit” that could be an indicator of leukemic transformation of MDS or AML in patients with FPD/AML.


Leukemia ◽  
2009 ◽  
Vol 24 (1) ◽  
pp. 242-246 ◽  
Author(s):  
M C J Jongmans ◽  
R P Kuiper ◽  
C L Carmichael ◽  
E J Wilkins ◽  
N Dors ◽  
...  

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4244-4244
Author(s):  
William N. Patton ◽  
Graeme Suthers ◽  
Meryl Altree ◽  
Catherine Carmichael ◽  
Ella Wilkins ◽  
...  

Abstract Aim To identify the causative heritable mutation in a family with autosomal dominant familial platelet disorder with predisposition to acute myeloid leukemia (FPD/AML). Method Confirmation of family pedigree, enrolment into ethics committee approved Australian Familial Hematological Cancer Study, procurement of genomic DNA from pedigree members and genetic analysis by sequencing of RUNX1 and CEBPA genes. Results The proband intially presented aged 50 with mild thrombocytopenia initially diagnosed as idiopathic thrombocytopenic purpura when bone marrow examination (including cytogenetics analysis) was normal. Three years later she was referred with severe progressive thrombocytopenia unresponsive to high dose steroids and intravenous immunoglobulin together with mild anemia and neutropenia. Marrow examination revealed subtle dysplasia with monosomy 7 in 12/20 metaphases. A diagnosis of myelodysplastic syndrome (MDS) was made. Three months later (Feb 2007), she progressed to acute myeloid leukemia (AML). The proband’s mother had had mild thrombocytopenia with subsequent MDS (aged 70) and died of AML two years later. The proband’s only sibling and nephew have mild thrombocytopenia without features of MDS. The proband entered cytogenetic remission following one course of AML induction therapy but continued to show dysplastic features. She then received 2 cycles of consolidation therapy and has undergone unrelated donor allogeneic stem cell transplant (July 2007). Sequencing of PCR products from exons of the RUNX1 gene identified a novel heterozygous mutation in the proband’s constitutional DNA: c.958C>T in exon 7, in the transactivation domain, causing a nonsense mutation, p.Arg293X (sequence variation for RUNX1 classified according to GenBank Accession No. NC_000021). The sibling has the same mutation and studies in other relatives are underway. Conclusion This study has identified a novel RUNX1 mutation responsible for FPD/AML in this family. Clinicians should be aware of this rare inherited disorder and the availability of genetic testing. People with mutations may be asymptomatic and genetic testing in such families is essential before considering bone marrow transplantation from a living related donor.


Platelets ◽  
2013 ◽  
Vol 25 (4) ◽  
pp. 300-302 ◽  
Author(s):  
Takashi Toya ◽  
Akihide Yoshimi ◽  
Takehiko Morioka ◽  
Shunya Arai ◽  
Motoshi Ichikawa ◽  
...  

Leukemia ◽  
2015 ◽  
Vol 30 (4) ◽  
pp. 999-1002 ◽  
Author(s):  
I Antony-Debré ◽  
N Duployez ◽  
M Bucci ◽  
S Geffroy ◽  
J-B Micol ◽  
...  

2016 ◽  
Vol 157 (8) ◽  
pp. 283-289
Author(s):  
Péter Attila Király ◽  
Krisztián Kállay ◽  
Dóra Marosvári ◽  
Gábor Benyó ◽  
Anita Szőke ◽  
...  

Myelodysplastic syndrome and acute myeloid leukaemia are mainly sporadic diseases, however, rare familial cases exist. These disorders are considered rare, but are likely to be more common than currently appreciated, and are characterized by the autosomal dominant mutations of hematopoietic transcription factors. These syndromes have typical phenotypic features and are associated with an increased risk for developing overt malignancy. Currently, four recognized syndromes could be separated: familial acute myeloid leukemia with mutated CEBPA, familial myelodysplastic syndrome/acute myeloid leukemia with mutated GATA2, familial platelet disorder with propensity to myeloid malignancy with RUNX1 mutations, and telomere biology disorders due to mutations of TERC or TERT. Furthermore, there are new, emerging syndromes associated with germline mutations in novel genes including ANKRD26, ETV6, SRP72 or DDX41. This review will discuss the current understanding of the genetic basis and clinical presentation of familial leukemia and myelodysplasia. Orv. Hetil., 2016, 157(8), 283–289.


2019 ◽  
Vol 152 (Supplement_1) ◽  
pp. S115-S115
Author(s):  
Kalpana Reddy

Abstract A 25-year-old female underwent emergent laparoscopic salpingectomy when she presented with an ectopic pregnancy (G1P0). A bone marrow biopsy performed for moderate persistent thrombocytopenia (60-105 K/μL) showed normocellularity, maturing trilineage hematopoiesis, and mildly increased morphologically normal megakaryocytes reported as consistent with idiopathic thrombocytopenic purpura (ITP). However, on further inquiry, the patient stated that her sister, father, paternal aunt, and paternal grandfather have/had low platelets. Her father had been diagnosed with myelodysplasia (MDS). Her paternal grandmother had died of acute myeloid leukemia (AML). Thus, although her marrow morphology revealed no evidence of overt dysplasia and despite her normal karyotypic study, a sample was sent for RUNX1 sequence analysis. A splice site mutation (c.967 + 2_967 + 5delTAAG) in RUNX1 was detected and initially interpreted as a somatic mutation. However, given the strong family history of thrombocytopenia and MDS/AML, a sample from her father was also sent for RUNX1 sequence analysis, and the identical intronic sequence variant in the RUNX1 gene was detected in him. This confirmed the RUNX1 mutation to be germline. In the context of autosomal dominant thrombocytopenia in the patient’s family, the finding of this variant in the affected patient and her similarly affected father was consistent with a pathogenic role. Since this patient was of reproductive age actively trying to have children, these molecular genetic findings had important implications. She elected to undergo in vitro fertilization in order to choose embryos without the RUNX1 mutation for implantation. Considering that her father and paternal grandmother developed MDS/AML, and because familial platelet disorder with predisposition to AML appears to show “anticipation,” she would require close future monitoring for blastic transformation. This case illustrates the significance of careful history taking and high suspicion index that can lead to simplified targeted cost-effective molecular testing resulting in the correct diagnosis without necessarily employing large gene panels.


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