Impact of molecular prognostic factors in cytogenetically normal acute myeloid leukemia at diagnosis and relapse.

Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Tet1 and Tet2 regulate 5-hydroxymethylcytosine production and cell lineage specification in mouse embryonic stem cells.ical labeling reveals the genome-wide distribution of 5-hydrox-ymethylcytosine. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Analysis of the ten-eleven translocation 2 (TET2) gene in familial myeloproliferative neoplasms. Clonal analysis of TET2 and JAK2 mutations suggests that TET2 can be a late event in the progression of myeloproliferative neoplasms. Bareford D, et al. Two routes to leukemic transformation after a JAK2 mutation-positive myeloproliferative neoplasm. W hile morphological evaluation of bone marrow and blood remains a cornerstone for the diagnosis of acute myeloid leukemia (AML), it is clear that the presence or absence of specific cytogenetic and molecular abnormalities is not only useful for determining overall prognosis, but is also used to guide treatment. However, while cytogenetic abnormalities present at diagnosis enable prediction of outcome and, in turn, stratification to risk-adapted treatments, clonal chromosomal aberrations are not detected in 40 to 50% of patients. 1 It is within this cyto-genetically normal (CN) group that the presence of acquired mutations, in addition to the expression of deregulated genes and non-coding RNA (i.e. microRNA), allows for molecular-risk classification of what has hitherto been a clinically heterogeneous subset of patients. 2-5 Indeed, the relevance of recurrent molecular abnormalities in CN-AML has been recently acknowledged by the inclusion of these markers within both the World Health Organization (WHO) and the European LeukemiaNet (ELN) classifications as a complement to cytogenetics. 6,7 Molecular analysis of markers that have been incorporated in both the WHO and ELN classifications (i.e., NPM1, FLT3 and CEBPA) is now routine. However, other mutated genes (e.g. WT1, IDH1/IDH2, TET2, RUNX1, MLL) or aberrantly expressed ones (e.g. BAALC, ERG, EVI1, miR-181a) will likely become useful in refining molecular risk in CN-AML. 8-21 Furthermore, as these molecular markers are not mutually exclusive, the prognostic impact of the different combinations of mutated and/or aberrantly expressed genes present within the same patient should be carefully evaluated to construct a molecular-risk score for practicing hematologists. The NPM1 gene encodes a protein that functions as a nucleus-cytoplasm chaperone and is involved in intracellu-lar processes including transport of pre-ribosomal particles, response to stress stimuli and DNA repair, and regulation of the activity and stability of tumor suppressors such as p53. 22 …