A novel pedigree with heterozygous germline RUNX1 mutation causing familial MDS-related AML: can these families serve as a multistep model for leukemic transformation?

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.

Figure 1

A new family with a heterozygous germline mutation in RUNX1. (a) Family pedigree. Circles, females; squares, males; black symbols, individuals with MDS-related AML, (II:6) 45,X,-Y[3]/46,XY[1], (III:3) 46,XX,add(2)(q36),del(5)(q14q34)[15]; gray symbols, history of non-hematological cancer; unfilled symbols, unaffected relatives; symbols with a diagonal line, deceased; numbers to the bottom left of symbols, individual identifiers; numbers above symbols, age at diagnosis (affected individuals), age (clinically healthy individuals), and age at death (deceased individuals); numbers in symbols, number of offspring; #, inconspicuous full blood cell count. (b) Electropherogram of sequence analysis of exon 3 of RUNX1 (NM_001001890.2) showing the heterozygous germline mutation c.520C>T, p.Arg174X (black arrow). The mutation was observed in DNA from bone marrow cells of the index patient and her father and in DNA from fibroblasts of the index patient. (c) Array-based comparative genomic hybridization (aCGH) analysis of leukemic cells (244k oligo-array, Agilent). Overview of aCGH results for II:6 (gray) and III:3 (blue) confirming the clonal loss of the Y chromosome (gray arrow) and the deletion of 5q (light blue arrow). In addition, indicative of a t(2;6)(q36;q23), a loss of 2q and a gain of 6q were detected (dark blue arrows). No further disease-associated copy number alterations were identified. (d) Detailed view of chromosome 6 indicating a gain in 6q, arr cgh 6q23.2qter(A_16_P37800109 → A_16_P17820807) × 3. (e) Metaphase fluorescence in situ hybridization of the index patient (III:3) using a locus-specific probe for MYB, located in 6q23 (ABBOTT, LSI MYB). Indicative of an unbalanced translocation t(2;6), there are two signals for the normal chromosomes 6 (arrow) and an additional signal for the derivative chromosome 2 (arrowhead).

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.


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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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Correspondence to B Schlegelberger.

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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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