TET2: A cornerstone in normal and malignant hematopoiesis

Abstract

Epigenetic modifiers that regulate DNA cytosine methylation and histone methylation/acetylation are recurrent targets of genetic aberrations in hematological malignancies. 1 Ten-eleven translocation 2 (TET2) is one of the TET family proteins that either catalyzes serial oxidation of 5-methylcytosine (5mC) or mediates histone modifications. 2-6 Genomic studies have uncovered recurrent TET2 loss-of-function mutations in various hematological malignancies as well as in clonal hematopoiesis of indeterminate potential (CHIP), 7-17 suggesting a critical role for TET2 in both normal and malignant hematopoiesis. In this review, we will summarize the most recent updates regarding TET2 biology, focusing on its key roles in hematopoietic stem cell (HSC) self-renewal/differentiation, inflammatory response, and leukemogenesis.

Tet2-mediated DNA demethylation regulates the proliferation and apoptosis of human leukemia K562 cells

“…DNA methylation plays key regulatory roles in mammalian development [13], retrotransposon silencing, genomic imprinting [14], X chromosome inactivation, and cancer. Cancer cells display highly dysregulated DNA methylation pro les characterized by global hypomethylation and hypermethylation of CpG islands in promoter [2]. The aberrant methylation is often associated with dysregulated expression of tumor suppressor genes and genomic instability [15,16].…”

“…DNA methylation is a extensively characterized modi cation of chromatin that often occurs at the 5carbon on cytosine residues in CpG dinucleotides [1]. It plays an fundamental role in many important biological process such as mammalian development, stem cell maintenance, cell proliferation/differentiation [2]. It was also involved in cancer which is studied by numerous research and abnormal methylation has been often linked to tumorigenesis [3].…”

O-GlcNAcylation: Implications in normal and malignant hematopoiesis

“…TET family proteins (TET1-3) play a critical role in DNA demethylation by converting 5-methylcytosine to 5-hydroxymethylcytosine, the initial step of DNA demethylation. Functional loss of TET proteins has been reported to enhance the self-renewal capacity of HSCs and induces skewed differentiation to the myeloid lineage [89], which helps to promote clonal expansion and transformation of HSC clones harboring TET mutations [90,91]. The tumor suppressor function of TET2 in hematologic malignancies has been reported by many studies with mice harboring combined mutation in Tet2 and various pathogenic genes such as in signaling or epigenetic regulation [92−94].…”

Desarrollo y caracterización de un modelo de ratón doble mutante en U2af1 y Tet2 para el estudio de los Síndromes Mielodisplásicos.

“…149 Por otro lado, en la vía activa los productos derivados de la oxidación de la 5mC, actúan como sustratos de distintas rutas de reparación que finalizan con la sustitución de la citosina metilada por una citosina sin modificaciones. [150][151][152] Además, se ha observado que la proteína TET2 también participa en la regulación transcriptómica y la modificación de histonas colaborando con complejos como la transferasa N-acetilglucosamina O-ligada (OGT) y desacetilasas de histonas (HDACs). 153 En conjunto, las proteínas TET regulan la autorenovación y la diferenciación de las HSC adultas y embrionarias.…”

“…Se han generado diversos modelos de ratón con mutaciones en Tet2 en concurrencia con alteraciones en otros genes como Dnmt3A, 187 Flt3, 188 Asxl1, 189 Bcor, 190 Sf3b1, 191 N-RAS, 186 y Jak2, 192 entre otros 151 . Sin embargo, todavía no se ha estudiado in vivo el efecto que poseen las alteraciones simultáneas de Tet2 y U2af1, a pesar de presentarse habitualmente en un 13 % de los pacientes con U2AF1 mutado.…”