Molecular pathogenesis of progression to myeloid leukemia from TET-insufficient status

Loss-of-function mutations in ten-eleven translocation-2 (TET2) are recurrent events in acute myeloid leukemia (AML) as well as in preleukemic hematopoietic stem cells (HSCs) of age-related clonal hematopoiesis. TET3 mutations are infrequent in AML, but the level of TET3 expression in HSCs has been found to decline with age. We examined the impact of gradual decrease of TET function in AML development by generating mice with Tet deficiency at various degrees. Tet2f/f and Tet3f/f mice were crossed with mice expressing Mx1-Cre to generate Tet2f/wtTet3f/fMx-Cre+ (T2DeltaT3), Tet2f/fTet3f/wtMx-Cre+ (DeltaT2T3), and Tet2f/fTet3f/fMx-Cre+ (DeltaT2DeltaT3) mice. All DeltaT2DeltaT3 mice died of aggressive AML at a median survival of 10.7 weeks. By comparison, T2DeltaT3 and DeltaT2T3 mice developed AML at longer latencies, with a median survival of approximately 27 weeks. Remarkably, all 9 T2DeltaT3 and 8 DeltaT2T3 mice with AML showed inactivation of the remaining nontargeted Tet2 or Tet3 allele, respectively, owing to exonic loss in either gene or stop-gain mutations in Tet3. Recurrent mutations other than Tet3 were not noted in any mice by whole-exome sequencing. Spontaneous inactivation of residual Tet2 or Tet3 alleles is a recurrent genetic event during the development of AML with Tet insufficiency.