Dissecting TET2 Regulatory Networks in Blood Differentiation and Cancer

Simple Summary Bone marrow disorders such as leukemia and myelodysplastic syndromes are characterized by abnormal healthy blood cells production and function. Uncontrolled growth and impaired differentiation of white blood cells hinder the correct development of healthy cells in the bone marrow. One of the most frequent alterations that appear to initiate this deregulation and persist in leukemia patients are mutations in epigenetic regulators such as TET2. This review summarizes the latest molecular findings regarding TET2 functions in hematopoietic cells and their potential implications in blood cancer origin and evolution. Our goal was to encompass and interlink up-to-date discoveries of the convoluted TET2 functional network to provide a more precise overview of the leukemic burden of this protein. Cytosine methylation (5mC) of CpG is the major epigenetic modification of mammalian DNA, playing essential roles during development and cancer. Although DNA methylation is generally associated with transcriptional repression, its role in gene regulation during cell fate decisions remains poorly understood. DNA demethylation can be either passive or active when initiated by TET dioxygenases. During active demethylation, transcription factors (TFs) recruit TET enzymes (TET1, 2, and 3) to specific gene regulatory regions to first catalyze the oxidation of 5mC to 5-hydroxymethylcytosine (5hmC) and subsequently to higher oxidized cytosine derivatives. Only TET2 is frequently mutated in the hematopoietic system from the three TET family members. These mutations initially lead to the hematopoietic stem cells (HSCs) compartment expansion, eventually evolving to give rise to a wide range of blood malignancies. This review focuses on recent advances in characterizing the main TET2-mediated molecular mechanisms that activate aberrant transcriptional programs in blood cancer onset and development. In addition, we discuss some of the key outstanding questions in the field.