Mutation analysis for RUNX1, MLL-PTD, FLT3-ITD, NPM1 and NRAS in 269 patients with MDS or secondary AML

Engineering mouse models with myelodysplastic syndrome human candidate genes; how relevant are they?

“…122,123 Nevertheless, several transcription factor genes have been reported to be mutated or truncated in MDS, including RUNX1 (AML1), CBFb, C/EBPa, TEL, MLL, EVI1, RARa, P53, IRF-1, and SALL4. 7 Both point mutations in the RUNT domain and truncation of the C-terminus domain of the RUNX1 (AML1) gene are found in 15-40% of MDS patients with excess blasts. 7 Mice expressing the RUNX1 (AML1) S291fs mutation develop MDS with excess blasts and erythroid dysplasia.…”

“…7 Both point mutations in the RUNT domain and truncation of the C-terminus domain of the RUNX1 (AML1) gene are found in 15-40% of MDS patients with excess blasts. 7 Mice expressing the RUNX1 (AML1) S291fs mutation develop MDS with excess blasts and erythroid dysplasia. 51 TEL has been discussed above.…”

“…55 CBFb-MYH11 transgenic mice expressing the fusion protein under the control of the MRP8 promoter have been reported to develop dysgranulopoiesis 115 whereas the CBF-MYH11 KI mouse model develops AML. 56 Chromosomal translocations involving MLL, such as t(11;16)(MLL-CBP) 58,59 and t(11;19), 57 as well as MLL gene tandem duplications (MLL-PTD), 7 have been described in MDS and t-MDS, although frequencies are low. However, none of the MLL-AF9 mouse models, whether it be KI 61 or retroviral BM transduction/transplantation assay (rt/BMT) models, appear to develop MDS, and overt AML rapidly develops.…”

“…Cytogenetic abnormalities are relatively frequent in MDS; deletions and rare chromosomal reciprocal translocations have been identified, while DNA sequencing and micro-arrays (RNA, CGH) have confirmed additional mutations and deletions. 7,8 Thus, genetic and epigenetic abnormalities are linked to MDS pathogenesis. 9 Efforts have been made to develop accurate animal models of MDS that would help us understand the pathogenesis of the disease and the mechanisms of its transformation to AML.…”

Karyotype evolution and acquisition of FLT3 or RAS pathway alterations drive progression of myelodysplastic syndrome to acute myeloid leukemia

“…FLT3 and NRAS mutations are thought to be important genetic events contributing to the pathogenesis of AML 4-6 and the expected increase in the frequencies of mutations in s-AML cases was observed, confirming previously reported data. 7,8 In an very elegant study, recently published by Lindsley et al, the three different AML subtypes -secondary, therapy-related and de novo -were genetically compared and also in a small group of 17 MDS/s-AML matched samples the authors showed that 78% of the patients gained mutations in transcription factors as well as signal transduction proteins (FLT3 and RAS pathway) during s-AML transformation. 9 These results are in line with our data showing predominantly acquired mutations in signal transduction.…”