The prognostic significance of bone marrow levels of neurofibromatosis‐1 protein and ras oncogene mutations in patients with acute myeloid leukemia and myelodysplastic syndrome

Abstract

BACKGROUNDIt has been reported that point mutations of the ras gene occur frequently in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). However, the prognostic significance of ras gene mutations in patients with these disorders has been a controversial issue. Although abnormalities in the neurofibromatosis 1 (NF1) gene, which is a gene involved in the ras pathway, have been observed frequently in patients with juvenile chronic myelogenous leukemia, the role of these abnormalities in adult patients with AML or MDS is not clear.METHODSIn this study, bone marrow specimens that were obtained from previously untreated patients with AML and MDS were examined for ras mutations, and the levels of NF1 protein expression were measured.RESULTSRas point mutations were detected in 16 of 83 patients with AML (19%) and in 21 of 90 patients with MDS (23%). Fourteen of 28 patients with chronic myelomonocytic leukemia (50%) had ras gene mutations. Decreased bone marrow levels of NF1 protein (< 70% of the median level detected in control bone marrow specimens) were observed in 20 of 66 patients with AML (30.3%) and in 8 of 29 patients with MDS (27.6%); none of the patients with ras gene mutations had decreased bone marrow levels of NF1 protein. The presence of a mutant ras gene was associated with a shorter complete remission duration (CRD) in patients with MDS (P = 0.05) but had no effect on survival in patients with AML or MDS. Patients with AML who had decreased NF1 protein levels had a slightly longer CRD compared with patients who had normal NF1 levels (P = 0.07). However, the NF1 level had no significant impact on survival among patients with AML or MDS. When patients with low NF1 levels were grouped with patients who had ras mutations, the patients who had AML had a significantly longer CRD compared with the patients who had MDS (P = 0.02).CONCLUSIONSThe current results suggest that a reduction in NF1 protein expression and the presence of ras point mutations may complement each other and that they both play a complex role in the biology of AML and MDS. Cancer 2003;97:441–9. © 2003 American Cancer Society.DOI 10.1002/cncr.11036

Nf1 gene inactivation in acute myeloid leukemia cells confers cytarabine resistance through MAPK and mTOR pathways

“…Leukemias with NF1 mutations usually have a poor prognosis, and strikingly shorter complete remission durations have been noticed in AML patients bearing NF1 or RAS mutations. 5 Although the association between the ATP-binding cassette transporter MDR1/PGP and drug resistance in AML has been well documented, we found no detectable difference in the transcriptional level of Abcb1a, Abcb1b and Abcb4 between sensitive and resistant cells (data not shown). Instead, we found that the level of phosphorylated ERK was elevated in B106, B114 and B117 compared to other BXH-2 AML cell lines tested, but this is not the case for total ERK1/2, p21…”

DNA profiling analysis of 100 consecutive de novo acute myeloid leukemia cases reveals patterns of genomic instability that affect all cytogenetic risk groups

“…44 Recently, it has been described that affected children with NF1 may develop myeloid malignancies after losing their wild-type NF1 allele due to interstitial uniparental disomy. 45 To date, mutations in NF1 have not been identified in adult patients with any myeloid disorders 46 but, it has been recently demonstrated that hemizygotic NF1 mice are more sensitized to carcinogenic stimuli, which result in hematological disorders independent of mutation of Trp53. 47 The NF1 gene has also been shown to be downregulated by the AML1-ETO fusion gene, which represses NF1 gene expression, resulting in RAS overexpression.…”

Animal models of acute myelogenous leukaemia – development, application and future perspectives

“…Co-expression and interaction of NUP98-HOX9 with Meis1 has been shown to accelerate disease progression. 113 Finally, patients exhibiting mutations in the Nf1 45,87,114 tumour suppressor gene with Ras mutations had markedly shorter complete remission durations, 107 through loss of functional regulation of Ras (p21 ras ) activation in response to GM-CSF. These examples accentuate the significance of transcriptional dysregulation and emphasise the importance of signalling pathways in human AML.…”

“…There is substantial homology between the genes mutated and identified by proviral tagging in mouse AML and those implicated in the human disease [100][101][102][103][104][105][106][107][108] as exemplified in the following cases. Firstly, the AML1(Cbfa2, Runx1, Pebp2aB) 84 oncogene targeted by chromosomal translocation t (8;21), in approximately 12% of AML cases, 109 has been shown to play a vital role in the regulatory expression of many genes involved in haematopoietic cell development.…”