Increased dosage of Runx1/AML1 acts as a positive modulator of myeloid leukemogenesis in BXH2 mice

Abstract

The RUNX1/AML1 gene on chromosome 21 is most frequently inactivated in human leukemias. In addition, an increased dose of RUNX1 is suggested as a basis for several kinds of leukemias. Amplifications of chromosome 21 or the RUNX1 gene are shown to be associated with leukemias with lymphoid lineage, whereas its involvement in myeloid lineage remains unclear. In this study, we generated GATA-1 promoter-driven Runx1 transgenic (Tg) mice, which showed a transient mild increase of megakaryocyte marker-positive myeloid cells but no spontaneous leukemia. These mice were then crossed with BXH2 mice, which have a replication-competent retrovirus in the mouse and develop myeloid leukemia due to insertional mutagenesis by random integration of the virus. Overexpressed Runx1 transgene in BXH2 mice resulted in shortening of the latency of leukemia with increased frequency of megakaryoblastic leukemia, suggesting that increased Runx1 dosage is leukemogenic in myeloid lineage. Identifications of retroviral integration sites revealed the genetic alterations that may cooperate with Runx1 overdose in myeloid leukemogenesis. This mouse model may be useful for analysing the pathogenesis of myeloid leukemias with RUNX1 overdose, especially to examine whether an extra-copy of RUNX1 by trisomy 21 is causally related to Down's syndrome-related acute megakaryoblastic leukemia (DS-AMKL).

RUNX3 protein is overexpressed in human basal cell carcinomas

“…Moreover, RUNX3 is also a downstream target of the TGF-b tumor suppressor pathway. Although all members of the RUNX family, most notably RUNX2, are known to promote tumorigenecity in mouse models (Cameron and Neil, 2004;Yanagida et al, 2005), our study implicates RUNX3 acting as a putative oncogene in human cancer.…”

MicroRNAs and genomic instability

“…11 and located 176 kb downstream of Nf1 (neurofibromatosis 1) is mmu-miR-193 which can be found in a cluster with four other miRNAs. Retroviral integration into Nf1 principally results in myeloid tumors [75,76,79,80]. The mmu-miRNA-142 is also found further distal on chr.…”

“…About 52 kb distal to Jak1 on chr. 4 is mmu-miR-101a; integration into the 5′ UTR region of Jak1 results in myeloid tumors [75,76]. On mouse chr.…”

Physical association of the patient-specific GATA1 mutants with RUNX1 in acute megakaryoblastic leukemia accompanying Down syndrome

“…12 Interestingly, a recent study showed that overexpression of the Runx1 gene in BXH2 mice, which have a replication-competent retrovirus, results in an increased frequency of megakaryoblastic leukemia, suggesting that increased RUNX1 dosage is leukemogenic in the myeloid lineage. 13 Recent reports have shown that GATA1 physically interacts with RUNX1. Elagib et al 12 showed that both the N-terminal (residues 1-85) and the C-terminal (residues 319-413) regions of mouse GATA1 are critical for binding RUNX1.…”