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

Abstract

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+ (T2ΔT3), Tet2f/fTet3f/wtMx-Cre+ (ΔT2T3), and Tet2f/fTet3f/fMx-Cre+ (ΔT2ΔT3) mice. All ΔT2ΔT3 mice died of aggressive AML at a median survival of 10.7 weeks. By comparison, T2ΔT3 and ΔT2T3 mice developed AML at longer latencies, with a median survival of ∼27 weeks. Remarkably, all 9 T2ΔT3 and 8 ΔT2T3 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.

TET2: A cornerstone in normal and malignant hematopoiesis

“…Although TET3 mutations are infrequent in hematological malignancies, its expression declines with age in mouse HSCs as well as in human peripheral blood T cells 71,72 . Consistent with this observation, both Tet2 +/− Tet3 −/− and Tet2 −/− Tet3 +/− mice developed lethal AML in vivo with spontaneous inactivation of residual nontargeted Tet2 or Tet3 allele, respectively, suggesting that this phenomenon is a recurrent genetic event during myeloid transformation with Tet insufficiency 73 …”

“…71,72 Consistent with this observation, both Tet2 +/− Tet3 −/− and Tet2 −/− Tet3 +/− mice developed lethal AML in vivo with spontaneous inactivation of residual nontargeted Tet2 or Tet3 allele, respectively, suggesting that this phenomenon is a recurrent genetic event during myeloid transformation with Tet insufficiency. 73 F I G U R E 6 Mutual exclusivity and cooperativity of ten-eleven translocation 2 (TET2) mutation with other disease alleles. A, left panel, Wilms tumor 1 (WT1) physically interacts with and recruits TET2 to regulate its target gene expression through facilitating conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC).…”

Ten-eleven translocation proteins (TETs): tumor suppressors or tumor enhancers?

“…Instead, a significant elevation of the TET1 expression level was detected in the patient tumor tissues with EGFR mutations. Thus, further studies are indispensable to explain the discrepancy between cancer cell lines and human cancer tissues [114].…”

Functional multigenic variations associated with hodgkin lymphoma

“…4 In the present study, we have observed the most significant SNP rs150945752 at the MEGF11 (multiple epidermal growth factor-like domains) gene, and the similar gene was reported to be upregulated in lung adenocarcinoma patients. 29 MEGF11 and other genes such as Catenin α 1 (CTNNA1), containing the 1b (SETD1B), membrane organizing extension spike protein (MSN), and Olfactory receptor (OLFR152) have been identified in human acute myeloid leukemia cells [30][31][32][33][34][35][36][37] and, consequently, observed some contribution. The second-most significant gene is CACNA1I with the SNP, rs58055559, associated with the HL patients.…”