The runt-related transcription factor 1 (RUNX1) encodes for an α-subunit of the core-binding factor and is known as the key regulator in myeloid cells. Heterozygous germline mutations in RUNX1 were identified as a causative genetic alteration leading to a familial platelet disorder with propensity to myeloid malignancies (FPD/MM). For the development of overt leukemia, secondary alterations are required.1 To discuss the potential use of FPD/MM as a multistep model for leukemic transformation in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), we report here on a female index patient and her father, who both developed MDS-related AML (MDR-AML) with differing clinical course caused by a heterozygous germline mutation in RUNX1 and different secondary chromosomal aberrations.
The 13-year-old female index patient (III:3, Figure 1a) was diagnosed with MDR-AML after a brief history of anemia. Subsequently, she underwent hematopoietic stem cell transplantation (HSCT) from an unrelated donor. Sibling donor HSCT was avoided as MDR-AML was diagnosed in her 47-year-old father 6 months earlier (II:6, Figure 1a). The twin brother, one younger and one older brother of the index patient and their mother are clinically healthy. No history of thrombocytopenia or platelet defects was reported in the family.
Analysis of RUNX1 identified the heterozygous germline mutation c.520C>T, p.Arg174X in the index patient and her father (Figure 1b). The frameshift mutation with a predicted dominant negative effect2 was earlier found in another family with FPD/MM and a sporadic case of atypical CML with acquired trisomy 21.3, 4
Chromosome analysis of bone marrow cells from our index patient showed a deletion of 5q (del(5q)) and a structural aberration of 2q. Array-based comparative genomic hybridization (aCGH) confirmed the del(5q) and pointed to an unbalanced translocation t(2;6)(q36;q23) (Figures 1c and d), finally confirmed by fluorescence in situ hybridization using a specific probe for v-myb myeloblastosis viral oncogene homolog, avian (MYB) (Figure 1e). In contrast, the only aberration identified in bone marrow cells of the diseased father was a loss of the Y chromosome (–Y) (Figure 1c). Whereas –Y is a typical chromosome aberration of adult MDS associated with a good prognosis, del(5q) is rarely seen in childhood MDS and usually occurs within complex clones associated with a more unfavorable prognosis. In our index patient, the gain of 6q led to an additional copy of the proto-oncogene MYB, an essential transcription factor in hematopoietic cells.5 Genetic alterations involving MYB, including locus duplication, were earlier found in a subset of T-acute lymphoblastic leukemia.6 In addition, Zhao et al.7 recently reported on a negative feedback loop between MYB and miR-15a located in 13q14, a region frequently deleted in myeloid and lymphocytic leukemia. Thus, MYB is an interesting candidate for leukemic transformation that may co-operate with heterozygous germline mutations in RUNX1 and del(5q).
Although heterozygous mutations in RUNX1 are not sufficient for leukemogenesis,1, 2 somatically acquired secondary events may promote transformation leading to overt MDS and AML. As seen in the reported family, recruitment of different secondary alterations may partially explain the variable penetrance and clinical heterogeneity seen in FPD/MM. Cytogenetic investigations of leukemia patients with FPD/MM displayed chromosomal aberrations that frequently occur in sporadic MDS/AML, and vice versa, RUNX1 mutations were seen in sporadic MDS/AML.1 Consequently, rare FPD/MM-related myeloid malignancies may serve as a model for multistep leukemogenesis in MDS/AML8 and, as illustrated here, aCGH may help to identify candidate genes involved in malignant transformation in familial and sporadic myeloid malignancies.
Conflict of interest
The authors declare no conflict of interest.
Osato M, Yanagida M, Shigesada K, Ito Y . Point mutations of the RUNX1/AML1 gene in sporadic and familial myeloid leukemias. Int J Hematol 2001; 74: 245–251.
Michaud J, Wu F, Osato M, Cottles GM, Yanagida M, Asou N et al. In vitro analyses of known and novel RUNX1/AML1 mutations in dominant familial platelet disorder with predisposition to acute myelogenous leukemia: implications for mechanisms of pathogenesis. Blood 2002; 99: 1364–1372.
Song WJ, Sullivan MG, Legare RD, Hutchings S, Tan X, Kufrin D et al. Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nat Genet 1999; 23: 166–175.
Preudhomme C, Warot-Loze D, Roumier C, Grardel-Duflos N, Garand R, Lai JL et al. High incidence of biallelic point mutations in the Runt domain of the AML1/PEBP2 alpha B gene in Mo acute myeloid leukemia and in myeloid malignancies with acquired trisomy 21. Blood 2000; 96: 2862–2869.
Ramsay RG, Gonda TJ . MYB function in normal and cancer cells. Nat Rev Cancer 2008; 8: 523–534.
Clappier E, Cuccuini W, Kalota A, Crinquette A, Cayuela JM, Dik WA et al. The C-MYB locus is involved in chromosomal translocation and genomic duplications in human T-cell acute leukemia (T-ALL), the translocation defining a new T-ALL subtype in very young children. Blood 2007; 110: 1251–1261.
Zhao H, Kalota A, Jin S, Gewirtz AM . The c-myb proto-oncogene and microRNA-15a comprise an active autoregulatory feedback loop in human hematopoietic cells. Blood 2009; 113: 505–516.
Niimi H, Harada H, Harada Y, Ding Y, Imagawa J, Inaba T et al. Hyperactivation of the RAS signaling pathway in myelodysplastic syndrome with AML1/RUNX1 point mutations. Leukemia 2006; 20: 635–644.
We thank the patients for their participation in this study, Friederike Grundstedt and Marcel Tauscher for their expert technical assistance, and Gillian Teicke for her assistance in editing the paper. This work was supported by the European Genomic and Epigenetic Study on MDS and AML (EuGESMA) COST action network. TR was supported by a grant from the MD/PhD Program Molecular Medicine, Hannover Medical School.
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Ripperger, T., Steinemann, D., Göhring, G. et al. A novel pedigree with heterozygous germline RUNX1 mutation causing familial MDS-related AML: can these families serve as a multistep model for leukemic transformation?. Leukemia 23, 1364–1366 (2009) doi:10.1038/leu.2009.87
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