**5. HIF and epigenetic modification in myeloid leukemia**

promoting association between HIF and p300. (2) SWI/SNF are complementary gene promoters of HIF-1α, which is a requirement for the expression of HIF-1α mRNA. The regulation of SWI/SNF could also describe the profound effects of HIF-dependent responses on hypoxia. On the other hand, the SWI/SNF complex alters the chromatin structure in some HIF target promoters or enhancers, thereby favoring their expression. (3) Hypoxia activates JMJD1A which promote a decrease in H3K9me2. In the meantime, oxygen deprivation also inhibits JARID1A histones demethylases which provoke an increase in H3K4me2 levels at their target promoters, thus enhancing gene expression. In addition, hypoxia increases H3K4me3 and H3K27me3 levels in some HIF target promoters, and hypoxia-inductive H3K4me3 seems to depend on the inhibitory effects of histone demethylase [38]. The hypoxia-inducible gene promoter was also observed in EPO, HMOX1, and DAF [39, 40]. (4) The interaction between Reptin and HIF1-α is enhanced in hypoxia, leading to recruitment of HDAC1 to some HIF target genes, negatively regulating their transcription (**Figure 2**). However, more research is still needed to fully understand its biological functions and to identify the enzymes involved in signal transduction pathways. It provides holistic assessment regarding hypoxia on the

epigenetic modifications.

112 Myeloid Leukemia

**Figure 2.** HIF regulated epigenetic changes in response to hypoxia.

Metabolic flexibility relies on the rewiring of the existing metabolic pathways, which are closely controlled by "pathway switch proteins," to efficient rerouting of metabolites selected by cellular needs. As discussed earlier, HIF controls many aspects of tumor in terms of location, size, cell type, or local invasion. Other aspects, like state of differentiation and hierarchical nature, were also regulated by HIF. Most tumor-initiating mutations occur in stem cell or progenitor populations. The expansion of these mutant cells with a more differentiated phenotype that usually characterizes individual cancers are responsible for the cause of pathogenesis. This was first described in 1997 for acute myeloid leukemia and subsequently extended to solid tumors, including melanoma, Glioblastoma (GBM), and pancreatic cancer [41, 42].

Limited oxygen access is the common feature in solid tumor due to inadequate tissue perfusion, thus, cancer metabolism is heavily influenced by adaptation to highly hypoxic microenvironment. In many cases, HIF is involved as a master regulator. Recently, an increasing number of other proteins, regulated by HIF, are found to influence energy metabolism. In addition, a series of mutations in these proteins—for example, SDH, FH, isocitrate dehydrogenase (IDH), activation-induced cytosine deaminase (AID), or drive altered metabolism. These findings have supported the notion that HIF has a role to play in oncology, and affects diagnostic methods and drug discovery.

In hematological tumors, bone marrow and lymph nodes represent hypoxic environments. The quiescent hematopoietic stem cells (HSCs) in the bone marrow existing in the hypoxic niche utilization of predominantly glycolysis pathway are regulated by HIF-1α stabilization [21]. Hypoxia modulates mitochondrial respiration in an HIF-1α-dependent manner. HIF promoter, the expression of pyruvate dehydrogenase kinase-1 (PDK1), in turn, inhibits pyruvate dehydrogenase (PDH) [43]. In addition, PKD1 activation is also important in inducing pluripotent stem cell, as evidenced by four Yamanaka factors (OCT4, SOX2, KLF4, and c-MYC) sufficient to upregulate PDK1, and initiates a Warburg-like metabolic rewiring which is closely linked with conversion of pluripotency [44]. On the other hand, metabolic reprograming initially triggered by HIF stabilizes HIF expression independently of oxygen to gain tumor survival advantage. As an example, imatinib-resistant cell expresses high levels of HIF-1αs and induces BCR-ABL upregulation [45]. Recent study further suggests that HIF is the potential cause to trigger gene translocation through limiting activation-induced cytosine deaminase (AID) expression [46, 47]. In the therapeutic point of view, the stem cell nature of cancer is also reflected in removing differentiation block therapy. For example, all-*trans* retinoic acid combined with cytotoxic drug was used in the clinical practice for the treatment of acute promyelocytic leukemia (APL) [48]. Other promoting differentiation agent aurora kinase A inhibitors were shown effective in acute megakaryocytic leukemia [49].

Other feature of leukemia cell is attenuated metabolic pathway in glycolysis even in aerobic conditions [50]. Leukemic cells, other than solid tumors, have the advantage to access oxygen; however, levels of HIF-1α, GLUT1, GLUT3, and CA4 are still significantly enhanced compared to normal blood cells. Clinical evidence shows that higher glycolytic rate in leukemic cells induces resistance to chemotherapeutics. Instead, inhibition of glycolysis using 2-deoxyglucose (2DG) promotes leukemic cell susceptibility to chemotherapeutic treatment, resulting in induction of leukemic cell death in normoxia [51].

[8] Bruick RK, McKnight SL. A conserved family of prolyl-4-hydroxylases that modify

HIF-Regulated Leukemogenesis Through the Advances on Epigenetic Mechanism

http://dx.doi.org/10.5772/intechopen.75769

115

[9] Jaakkola P et al. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation com-

[10] Gossage L, Eisen T, Maher ER. VHL, the story of a tumour suppressor gene. Nature

[11] Lando D, Peet DJ, Whelan DA, Gorman JJ, Whitelaw ML. Asparagine hydroxylation of

[12] Pouyssegur J, Dayan F, Mazure NM. Hypoxia signalling in cancer and approaches to

[13] Selak MA et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-

[14] Isaacs JS et al. HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: Novel role of fumarate in regulation of HIF stability. Cancer Cell.

[15] Peyssonnaux C et al. Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs). The Journal of Clinical Investigation. 2007;**117**:1926-1932

[16] Semenza GL, Roth PH, Fang HM, Wang GL. Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. The Journal of Biological

[17] Brahimi-Horn MC, Chiche J, Pouyssegur J. Hypoxia signalling controls metabolic

[18] Gillies RJ, Robey I, Gatenby RA. Causes and consequences of increased glucose metabo-

[19] Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: The

[20] Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis? Nature Reviews.

[21] Suda T, Takubo K, Semenza GL. Metabolic regulation of hematopoietic stem cells in the

[22] Ullah MS, Davies AJ, Halestrap AP. The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1alpha-dependent mecha-

[23] Shimoda LA, Fallon M, Pisarcik S, Wang J, Semenza GL. HIF-1 regulates hypoxic induction of NHE1 expression and alkalinization of intracellular pH in pulmonary arterial

lism of cancers. Journal of Nuclear Medicine. 2008;**49**(Suppl 2):24S-42S

metabolic requirements of cell proliferation. Science. 2009;**324**:1029-1033

the HIF transactivation domain a hypoxic switch. Science. 2002;**295**:858-861

plex by O2-regulated prolyl hydroxylation. Science. 2001;**292**:468-472

enforce tumour regression. Nature. 2006;**441**:437-443

alpha prolyl hydroxylase. Cancer Cell. 2005;**7**:77-85

demand. Current Opinion in Cell Biology. 2007;**19**:223-229

nism. The Journal of Biological Chemistry. 2006;**281**:9030-9037

HIF. Science. 2001;**294**:1337-1340

Reviews. Cancer. 2015;**15**:55-64

Chemistry. 1994;**269**:23757-23763

Cancer. 2004;**4**:891-899

hypoxic niche. Cell Stem Cell. 2011;**9**:298-310

2005;**8**:143-153
