**1. Introduction**

Myeloid leukemia is the most prevalent leukemia in adults, including acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). AML is an aggressive hematologic malignancy that results in the disruption of normal self-renewal, differentiation, and hematopoietic stem and progenitor cell expansion leading to increased proliferation and accumulation of immature nonfunctioning myeloid progenitors. In turn, myeloid progenitors were blocked to

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

further differentiate into mature myeloid cell to play its role in the hematopoietic system. In comparison, in CML, hematopoietic stem cell is preferred to differentiate myeloid cells (leukemia cells). CML is much milder due to these leukemia cells still partial functions to maintain homeostasis. However, the leukemia cells uncontrollably divide, build up in the bone marrow, and spill over into the blood. Over time, the cells settle in other parts of the body, especially in the spleen (causing splenomegaly), and it can also promote into a fast-growing AML. The American Cancer Society reports that incidence rates have increased over the past few decades, estimating that in 2015 about 20,830 new cases of AML and 14,620 new cases of CML were diagnosed, and 10,460 deaths from AML and 4650 deaths from CML would occur in the USA [1]. Currently, the majority of AML patients still have a poor prognosis, making the development of novel therapies a priority. Prognosis is influenced by a combination of cytogenetic and genetic characteristics of the disease, together with clinical features and the patient's age. In the albeit heterogeneous genetic landscape of myeloid leukemia, many myeloid leukemia patients exhibit recurrent mutations in genes encoding epigenetic regulators [2]. It is thus becoming increasingly clear that epigenetic dysfunction plays a key role in leukemogenesis of AML and CML [3]. More importantly, the epigenetic regulators CREB-binding protein (CBP) and p300 histone acetyltransferases (HATs), as important HIF co-transcriptional factors, facilitate leukemogenesis and represent therapeutic targets in AML [4]. Here, we have focused on the effect of dysregulated epigenetic programs in the development and maintenance of myeloid leukemia. In addition, we have discussed recent advances in therapies specifically targeting these key epigenetic mechanisms.

splice variants [6]. HIF-2α is most abundantly expressed in the lung, followed by the heart, brain, liver, and various other organs. Despite their similarities in mediating transcriptional responses to hypoxia, HIF-1α and HIF-2α have distinct, nonredundant functions (reviewed in Semenza [2004] [7]). HIF-3α is the least-studied member of the family and has multiple splice variants [5]. The functional domains of HIF include DNA-binding region basic helix-loop-helix (bHLH), HIF dimerization-binding region PER-ARNT-SIM (PAS), oxygen tension modulated N-terminal transactivation domain (N-TAD), and C-terminal transactivation domain (C-TAD).

HIF-Regulated Leukemogenesis Through the Advances on Epigenetic Mechanism

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The regulation of HIF by the extent of oxygen pressure is dependent on the intermediator that affects HIF-α protein stability and/or its ability to bind cofactors essential for transcriptional activity. In normoxia, HIF-α is strictly controlled by two types of oxygen sensors. First, 2-oxoglutarate (2-OG)-dependent prolyl hydroxylase domain (PHD) proteins could hydroxylate two prolyl residues (Pro402 and/or Pro<sup>564</sup>) in the N-TAD of HIF-1α ODDD regions (**Figure 1**) [8, 9]. Currently, three functional 2-OG-dependent PHD have been identified—PHD1, PHD2, and PHD3,—and all three require oxygen, Fe2+, and 2-OG as cofactors. This modification of HIF-α promotes its destruction by the proteasomal system through interaction with von Hippel-Lindau (VHL) protein, a component of an E3 ubiquitin ligase complex [10]. A second

HIF-α subunit also contains oxygen-dependent degradation domain (ODDD).

**2.2. Oxygen-dependent hypoxia-inducible factor regulation**

**Figure 1.** HIF-1α regulation and HIF-1α dependent gene expression under hypoxia.
