Higher PLA2G4A expression is associated with mutations in NRAS (P < .001), RUNX1 (P = .012), ASXL1 (P = .007), and EZH2 (P = .038), all of which are known to contribute to MDS development.
With the advent of next generation sequencing, recurrent somatic mutations in genes involved in epigenetic regulation (TET2, ASXL1, EZH2, DNMT3A, IDH1/2), RNA splicing (SF3B1, SRSF2, U2AF1, ZRSR2), DNA damage response (TP53), transcriptional regulation (RUNX1, BCOR, ETV6) and signal transduction (CBL, NRAS, JAK2) have been identified in MDS.
In phase 2, this study accrued patients with relapsed/refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS) with NRAS or KRAS mutations (cohort 1); patients with AML, MDS, or chronic myelomonocytic leukemia (CMML) with a RAS wild-type mutation or an unknown mutation status (cohort 2); and patients with CMML with an NRAS or KRAS mutation (cohorts 3).
In addition to the detection of mutations known to be associated with MDS in NRAS, KRAS, MPL, NPM1, IDH1, PTPN11, APC and MET, single nucleotide variants so far unrelated to MDS in STK11 (n=1), KDR (n=3), ATM (n=1) and JAK3 (n=2) were identified.
Recent studies are shedding light on the molecular basis of myelodysplasia and how mutations and epimutations can induce and promote this neoplastic process through aberrant transcription factor function (RUNX1, ETV6, TP53), kinase signalling (FLT3, NRAS, KIT, CBL) and epigenetic deregulation (TET2, IDH1/2, DNMT3A, EZH2, ASXL1, SF3B1, U2AF1, SRSF2, ZRSR2).
Screening of MDS patient bone marrow (BM) identified NRAS:BCL-2 co-localization in 64% cases, correlating with percentage BM blasts, apoptotic features and disease status (p<0.0001).
Accordingly, in addition to classical oncogenic abnormalities, such as p53 abnormalities, or NRAS mutation, various molecular abnormalities, such as TET2, RPS14, or c-CBL, have been identified and/or proposed as the novel candidates for molecular basis of the development and progression of MDS.
We compared the frequency of FLT3-length mutations (FLT3-LM), FLT3-TKD, MLL-partial tandem duplications (MLL-PTD), NRAS, and KITD816 in 381 patients with MDS refractory anemia with excess blasts [RAEB] n=49; with ringed sideroblasts [RARS] n=310; chronic monomyelocytic leukemia [CMML] n=22) and in 4130 patients with AML (de novo: n=3139; secondary AML [s-AML] following MDS: n=397; therapy-related [t-AML]: n=233; relapsed: n=361).
Our results show that one-third of MDS patients acquire activating mutations of FLT3 or N-ras gene during AML evolution and FLT3/ITD predicts a poor outcome in MDS.
We have analyzed 35 archival bone marrow samples of children with MDS for the presence of mutations in the first and second exons of the NRAS and KRAS2 genes.
We have analyzed 35 archival bone marrow samples of children with MDS for the presence of mutations in the first and second exons of the NRAS and KRAS2 genes.
Our results show that one-third of MDS patients acquire activating mutations of FLT3 or N-ras gene during AML evolution and FLT3/ITD predicts a poor outcome in MDS.
In this study, we describe a case of ANLL-M7 with a previous history of MDS presenting a complex karyotype 46,XX, t(4;11)(q21;q23),del(5)(q13q33),t(12;13)(p13;q21) and N-RAS point mutation.
This erythroid lineage dysplasia recapitulates one of the most common features of myelodysplastic syndrome, and for the first time provides a causative link between mutational activation of N-RAS and the pathogenesis of preleukemia.
We performed longitudinal analyses of chromosomes and studied the configuration of NRAS, TP53, NF1, and cFMS genes in 70 patients with myelodysplastic syndrome(MDS).
We performed a longitudinal analysis of the karyotypes and N-ras gene configuration of bone marrow cells in 35 patients with myelodysplastic syndrome (MDS).
These three MDS patients with p53 gene mutations and an MDS-derived erythroleukemia cell line that we had previously reported to carry a p53 gene mutation showed no N-ras gene mutations, suggesting heterogeneity in the oncogenic mechanism of MDS.