Evaluation of allelic strength of human TET2 mutations and cooperation between Tet2 knockdown and oncogenic Nras mutation

摘要

The TET2 (tet methylcytosine dioxygenase 2) gene encodes a methylcytosine dioxygenase that catalyses the hydrolysis of 5-methylcytosine (5mC) to 5-hydroxylmethylcytosine (5hmC) and promotes DNA demethylation through passive and active mechanisms (Shih et al, 2012). Loss-of-function mutations in TET2 are identified in patients with myeloid and lymphoid malignancies, and are particularly frequent in patients with chronic myelomonocytic leukaemia (CMML) (36-58%) (Shih et al, 2012). Consistent with the patient sequencing analysis, conditional knockout of Tet2 in mice dysregulates haematopoietic stem cell (HSC) function and promotes development of a myeloid malignancy closely resembling human CMML (Cimmino et al, 2011). Despite the high mutation frequency, the prognostic importance of TET2 mutations is unclear in many cases (Shih et al, 2012). We postulated that this could be due to the differential allelic strengths of distinct TET2 mutations (e.g. amorphic versus hypomorphic) and/or the influence of other concurrent genetic alterations.