RAR-Alpha-PML Fusion During APL
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RAR-Alpha-PML Fusion During APL

AMLs (Acute Myeloid Leukemias) are characterized with chromosomal translocations resulting in the formation of fusion proteins. Understanding PML (Acute Promyelocytic Leukemia Inducer) function has become an area of intense research because of its involvement in the pathogenesis of APL (Acute Promyelocytic Leukemia), a distinct subtype of Myeloid Leukemia. In the vast majority of APL case studies, the PML gene (on Chromosome-15) fuses to the RAR-Alpha gene (Retinoic Acid Receptor-Alpha) (on Chromosome-17) as a consequence of reciprocal and balanced chromosomal translocations. In the t(15;17) chromosomal translocation, which is specific for APL, PML is found in a reciprocal translocation with the RAR-Alpha resulting in the formation of PML-RAR-Alpha and RAR-Alpha-PML fusion proteins (Ref.1). In a normal cell Vitamin-A (all-trans-Retinol) from dietary sources is converted to all-trans-Retinoic Acid in the liver through Retinol Metabolism and all-trans-Retinoic Acid is translocated to tissues by CRABP (Cellular Retinoic Acid Binding Protein) where it regulates target genes by binding with RARs (Retinoic Acid Receptors). Retinoic Acid is the only metabolite of Vitamin-A which regulates gene expression and all-trans-Retinoic Acid, the Carboxylic Acid form of Vitamin-A is of biological significance since it has high circulating levels than other isomers of Retinoic Acid. Biologically active ligands for the RARs include all-trans-Retinoic Acid, 9-cis-Retinoic Acid among others. 13-cis-Retinoic Acid is not a ligand for the RARs, but, it is readily converted into a RAR ligand by intracellular reciprocal isomerization. Less is understood about the fate of intracellular all-trans-Retinoic Acid is its isomerization to 9-cis-Retinoic Acid and 13-cis-Retinoic Acid. The RARs have a conserved modular structure consisting of six regions from A-F, viz., AF-1 or A/B (Amino-Terminal Activating Factor-1 Transcriptional Activation) Domain; a zinc-finger DBD or C (DNA-Binding Domain); a CoR or D (Hinge/Corepressor Binding) Domain; a LBD or AF-2 or E (Ligand-Binding/Transcriptional Activation) Domain; and a variable F (Carboxyl-Terminal) Domain. In RAR the DBD binds to the RARE (Retinoic Acid Response Element) region in the DNA. The RAREs consists of DRs (Direct Repeats) of AGG/TTCA motif with a spacer region of (n)25. Upon Retinoic Acid binding, RAR-Alpha regulates Retinoic Acid mediated gene expression and transactivates PML target genes critical for the induction of Myeloid Hemopoietic Cells’ terminal differentiation (Ref.2 & 3).

Under normal conditions PML is a potential Tumor Suppressor and is involved in Cellular Senescence, a process that controls Oncogenic Signaling leading to normal Cell Growth and Survival. PML is the organizer of nuclear matrix domains, NBs (Nuclear Bodies), with a proposed role in Apoptosis control. PML being a member of the RBCC (RING-B-Box-Coiled-Coil) Protein Family, contains three Zinc Finger-Like domains (a RING Finger and two B-Boxes) and a Coiled-Coil Dimerization domain. PML organizes NBs by targeting proteins such as Sp100 (Nuclear Antigen-Sp100), p53, Rb (Retinoblastoma) or Daxx onto these domains. These domains are also known as PODs (PML Oncogenic Domain/Promyelocytic Oncogenic Domains). PML levels increase during both Ras-induced Senescence, leading to a dramatic increase in the size and number of PODs. Survival factors/Ras signaling induce Cellular Senescence by up-regulating PML gene expression though MAPK (Mitogen-Activated Protein Kinase) activation (Ref.4 & 5). PML is covalently modified and conjugated to SUMO1 (Small Ubiquitin Related Modifier-1). This enables PML to form NBs and enhances their interaction with other proteins. A specific dephosphorylation event triggered by As2O3 (Arsenic Trioxide) targets PML to the nuclear matrix to form Primary PML bodies. Sumolation then induces the maturation to Secondary PML bodies. In mature PML-NBs (or Secondary PML bodies), PML forms the outer shell and many proteins (Sp100, Rb, p53, Daxx, etc) are found within its electron clear core. DNA damage induced activation of p53-dependent Apoptosis requires PML. PML acts as a coactivator for p53 and increases acetylation of p53 by the transcriptional coactivator CBP (CREB-Binding Protein). This acetylation of p53 is reversed by Sirt (Sirtuin (Silent Mating Type Information Regulation-2 Homolog)) releasing p53 into p53 Pathway. PML associates with Daxx-mediated Apoptosis induced by Fas/FasL (Fas Ligand) and TNF (Tumor Necrosis Factor)/TNFR (Tumor Necrosis Factor Receptor) and regulates the transcriptional repressor activity of Daxx. PML acts with Rb and p53 to promote Ras-induced Senescence. PML-Sp100 NBs act against viral invasions. Mature PML-NBs are finally degraded by the 11S Proteasome Complex (Ref.6 & 7).

In APL cells due to t(15;17) chromosomal translocation the fusion protein PML-RAR-Alpha retains both DBD and LBD of RAR-Alpha, compete with normal RAR-Alpha for ligand binding and inhibits its transcriptional function through aberrant recruitment of HDACs (Histone Deacetylases). Recruitment of HDACs to PML also leads to inhibition of p53 activity and Sumolation. HDACs therefore, represent an ideal candidate for blocking the action of the fusion proteins (Ref.7). PML-RAR-Alpha and RAR-Alpha-PML fusion protein expression disrupts formation of NBs and paralyzes Tumor Suppression, Cellular Senescence, Mature PML degradation and normal Cell Growth and Survival. Co-expression of RAR-Alpha-PML with PML-RAR-Alpha thus results in an increase of Leukemia incidence and makes a cell more prone to pathogen invasions. all-trans-Retinoic Acid is a standard therapy for the management of APL. However, 13-cis-Retinoic Acid and 9-cis-Retinoic Acid implication reduce the incidence of secondary head and neck tumors and APL, respectively. It is apparent that PML is essential for critical tumor suppressive pathways that are deregulated in APL and therapies such as induction of Retinoic Acid and As2O3 can be helpful in restoring normal PML function in APL cells that can cause the reappearance of NBs, and the reversal of cellular transformation, effecting the curing process in APL subjects (Ref.8 & 9).