APL is associated with a specific balanced reciprocal translocation (in 98% of the cases) between the long arms of chromosomes 15 and 17, t(15,17)(q24.1;q21.2). This translocations result in the fusion of PML (promyelocyte) gene on chromosome 15 to the RAR? (retinoic acid receptor-?) gene on chromosome 17 (J. H. Park et al., 2011; Lavau and Dejean, 1994; Jurcic et al., 2001). RAR? is a nuclear protein receptor which binds to the retinoid X receptor to induce differentiation of myeloid lineage by recruiting transcription corepressor complexes (CoC) and induce gene transcription repression (Zeidan and Gore, 2014). PML is a negative regulator of cell growth by arresting the G1 phase of the cell cycle (Strudwick and Borden, 2002). The pro-apoptotic functions of PML are mediated by both p53 dependent and p56 independent mechanism. PML enhance p53 activation by phosphorylation and acetylation by recruiting it into PML-NBs. It also inhibits MDM2, which is a negative regulator of p53 (Bernardi and Pandolfi, 2003; Takahashi et al., 2004). PML-NBs are subnuclear organelles involved in a number of cellular processes related to tumour suppression (Chen et al., 2012). Researches revealed that the PML can interact with a series of proteins such as pRB, p53, mTOR, cJun, Akt, Daxx and Elf4e to regulate the homeostasis in immune response, repress cell proliferation and to regulate protein synthesis during cellular processes (Borden and Culjkovic, 2009; Möller and Schmitz, 2003).
Pathogenesis of coagulopathy
The main pathophysiological mechanisms behind the bleeding diathesis in APL are the procoagulant activity, fibrinolysis, proteolysis and cytokine storm during the disease condition (Choudhry and DeLoughery, 2012). The two procoagulants involved are tissue factor (TF) and cancer procoagulant (CP). These are expressed abundantly in APL which initiates the coagulation cascade. The leukaemic cells generate more procoagulants activity on TF than normal cells, which can be further intensified during the period of increased apoptosis of promyelocytes (this happens during early induction of chemotherapy). Thus the APL cell and their apoptosis can cause thrombogenic incidents in APL patients (J. Wang et al., 2001). Annexin 2 is a surface receptor found on promyelocytes cell surface which can bind to plasminogen and tissue plasminogen activator (tPA). High levels of tPA and plasminogen activators along with their inhibitor plasminogen activator inhibitor-1 (PAI-1) are found in APL patients. This explains the fibrinolytic activity and haemorrhage in APL patients (O’Donnell et al., 2013; Ikezoe, 2014). The platelets are activated by increased plasma P-selectin. The prothrombotic effects are exacerbated by increased leukocytes and endothelial adhesiveness (Zhao et al., 2000). The roles of cytokines are not well studied, but found to have increased level of IL-1?, IL-6 and tumor necrosis factor ? (TNF-?) in APL patients. IL-1 and TNF? upregulate TF expression (Kwaan and Cull, 2014; Ikezoe, 2014)