Implications of somatic mutations in the AML1 gene in radiation-associated and therapy-related myelodysplastic syndrome/acute myeloid leukemia

Abstract

Somatically acquired point mutations of AML1/RUNX1 gene have been recently identified in rare cases of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Moreover, germ line mutations of AML1 were found in an autosomal dominant disease, familial platelet disorder with predisposition to AML (FPD/ AML), suggesting that AML1 mutants, as well as AML1 chimeras, contribute to the transformation of hematopoietic progenitors. In this report, we showed that AML1 point mutations were found in 6 (46%) of 13 MDS patients among atomic bomb (A-bomb) survivors in Hiroshima. Unlike acute or chronic leukemia patients among A-bomb survivors, MDS patients exposed relatively low-dose radiation and developed the disease after a long latency period. AML1 mutations also were found in 5 (38%) of 13 therapy-related AML/MDS patients who were treated with alkylating agents with or without local radiation therapy. In contrast, frequency of AML1 mutation in sporadic MDS patients was 2.7% (2 of 74). Among AML1 mutations identified in this study, truncated-type mutants lost DNA binding potential and trans-activation activity. All missense mutations with one exception (Gly42Arg) lacked DNA binding ability and downregulated the trans-activation potential of wild-type AML1 in a dominant-negative fashion. The Gly42Arg mutation that was shared by 2 patients bound DNA even more avidly than wild-type AML1 and enhanced the trans-activation potential of normal AML1. These results suggest that AML1 point mutations are related to low-dose radiation or alkylating agents and play a role distinct from that of leukemogenic chimeras as a result of chromosomal translocations caused by sublethal radiation or topoisomerase II inhibitors. (Blood. 2003;101:673-680)

Alternative genetic pathways and cooperating genetic abnormalities in the pathogenesis of therapy-related myelodysplasia and acute myeloid leukemia

“…Subsequent studies have shown that point mutation of the AML1 or RUNX1 gene is a common abnormality in t-MDS, 13,18 and we observed a highly significant clustering of this abnormality in pathway I. 13 Thus, 38% of the patients in this pathway (15 cases) had AML1 mutations (Figure 1).…”

Transcriptional dysregulation during myeloid transformation in AML

“…Subsequent studies have confirmed the occurrence of RUNX1 point mutations in AML, predominantly in the M0 subtype (Preudhomme et al, 2000;Langabeer et al, 2002;Matsuno et al, 2003;Roumier et al, 2003;Silva et al, 2003). Whereas mutations in the C-terminal domain were believed for some time to cluster within the RUNT domain, mutations in the C-terminal region, outside the RUNT domain, have also been identified, predominantly in MDS-AML (Harada et al, 2003). Finally, RUNX1 mutations turned out to occur at least as frequent as the first mode of RUNX1 alterations, namely, t(8;21), inv(16) and t(12;21), in secondary MDS-AML (Harada et al, 2003).…”

“…Whereas mutations in the C-terminal domain were believed for some time to cluster within the RUNT domain, mutations in the C-terminal region, outside the RUNT domain, have also been identified, predominantly in MDS-AML (Harada et al, 2003). Finally, RUNX1 mutations turned out to occur at least as frequent as the first mode of RUNX1 alterations, namely, t(8;21), inv(16) and t(12;21), in secondary MDS-AML (Harada et al, 2003).…”

Myeloid neoplasms with germ line RUNX1 mutation

“…Indeed, RUNX1 mutations have frequently been identified in patients with MDS and AML [6,7]. Furthermore, a higher frequency of RUNX1 mutations (30-50%) has been reported in therapyrelated and radiation-associated MDS and AML [13][14][15]. In general, RUNX1 mutations are considered to result in the loss of RUNX1 functions.…”