Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: PML
Cytogenetic location: 15q24.1 Genomic coordinates (GRCh38): 15:73,994,716-74,047,827 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q24.1 | Leukemia, acute promyelocytic, PML/RARA type | 3 |
The PML tumor suppressor protein is essential for the formation of a dynamic macromolecular nuclear structure called the PML-nuclear body (PML-NB). PML-NBs have also been referred to as nuclear domains-10, Kremer bodies, and PML oncogenic domains. Unlike more specialized subnuclear structures, PML-NBs are involved in diverse cellular functions, including sequestration and release of proteins, mediation of posttranslational modifications, and promotion of nuclear events in response to various cellular stresses. The PML gene is involved in the t(15;17) translocation of acute promyelocytic leukemia (APL; 612376), which generates the oncogenic fusion protein PML-retinoic acid receptor-alpha (RARA; 180240). PML-NBs are disrupted in APL and are thus implicated in APL pathogenesis (Bernardi and Pandolfi, 2007; Salomoni et al., 2008).
In the process of analyzing the RARA gene in the t(15;17)(q22;q11.2-q12) translocation specifically associated with APL, de The et al. (1990) identified a novel gene on chromosome 15 involved with the RARA gene in formation of a fusion product. This gene, which they called MYL for 'myelocytic leukemia,' was transcribed in the same direction as RARA on the translocated chromosome. De The et al. (1990) identified a 144-bp region, flanked by canonical splice acceptor and donor sequences, that had a high probability of being an exon and showed no significant similarity to any sequence in a protein data bank, thus suggesting that MYL is a previously undescribed gene. In a later report, de The et al. (1991) changed the name of the gene from MYL to PML. They reported, furthermore, that the gene product contains a novel zinc finger motif common to several DNA-binding proteins.
Goddard et al. (1991) demonstrated that PML is a putative zinc finger protein and potential transcription factor that is commonly expressed, with at least 3 major transcription products.
Goddard et al. (1995) cloned the murine Pml gene. The predicted amino acid sequence of mouse Pml, a ring-finger protein, shows 80% similarity to that of the human homolog, with greater than 90% similarity in the proposed functional domains.
The PML gene maps to chromosome 15q22 (de The et al., 1990).
Goddard et al. (1995) mapped the mouse Pml gene to a region of chromosome 9 with known homology of synteny to the region of 15q where PML is located.
While PML does not colocalize with proliferating cell nuclear antigen (PCNA; 176740) or spliceosomes, Dyck et al. (1994) showed that it is part of a macromolecular structure, composed of at least 4 nuclear proteins, that is adhered to the nuclear matrix. This structure shows a labeling pattern resembling spheres that vary in both size and number among individual cells of a given cell line. PML-RAR expression appears to disrupt the integrity of these structures (referred to by Dyck et al. (1994) as PML oncogenic domains, or PODs) and thus appears to be the possible cause of their altered morphology. Retinoid treatment leads to a striking reassembly of the POD, which in turn is linked to differentiation of the leukemic cells. These results identified a novel macromolecular nuclear structure and suggested that it may serve as a target of cellular transformation.
From their analysis of the phosphoamino acids of the PML protein, Chang et al. (1995) concluded that both tyrosine and serine residues are phosphorylated. To investigate whether expression of the PML protein is cell cycle related, HeLa cells synchronized at various phases of the cell cycle were analyzed by immunofluorescence staining and confocal microscopy. They found that PML was expressed at a lower level in S, G2, and M phases and at a significantly higher level in G1 phase. Other studies showed that PML is a phosphoprotein and is associated with the nuclear matrix. Chang et al. (1995) noted that PML shares many properties with tumor suppressors such as RB (614041).
Fusion of PML and TIF1A (603406) to RARA and BRAF (164757), respectively, results in the production of PML-RAR-alpha and TIF1-alpha-B-RAF (T18) oncoproteins. Zhong et al. (1999) showed that PML, TIF1-alpha, and RXR-alpha (180245)/RAR-alpha function together in a retinoic acid-dependent transcription complex. Zhong et al. (1999) found that PML acts as a ligand-dependent coactivator of RXR-alpha/RARA-alpha. PML interacts with TIF1-alpha and CREB-binding protein (CBP; 600140). In PML -/- cells, the retinoic acid-dependent induction of genes such as RARB2, and the ability of TIF1-alpha and CBP to act as transcriptional coactivators on retinoic acid, are impaired. Zhong et al. (1999) showed that both PML and TIF1-alpha are growth suppressors required for the growth-inhibitory activity of retinoic acid. T18, similar to PML-RAR-alpha, disrupts the retinoic acid-dependent activity of this complex in a dominant-negative manner, resulting in a growth advantage. PML-RAR-alpha was the first example of an oncoprotein generated by the fusion of 2 molecules participating in the same pathway, specifically the fusion of a transcription factor to one of its own cofactors. Since the PML and RAR-alpha pathways converge at the transcriptional level, there is no need for a double-dominant-negative product to explain the pathogenesis of APL.
Pearson et al. (2000) reported that the tumor suppressor PML regulates the p53 response to oncogenic signals. Pearson et al. (2000) found that oncogenic RAS (190020) upregulates PML expression, and that overexpression of PML induces senescence in a p53-dependent manner. p53 is acetylated at lysine-382 upon RAS expression, an event that is essential for its biologic function. RAS induces relocalization of p53 and the CBP acetyltransferase within the PML nuclear bodies and induces the formation of a trimeric p53-PML-CBP complex. Lastly, RAS-induced p53 acetylation, p53-CBP complex stabilization, and senescence are lost in PML -/- fibroblasts. Pearson et al. (2000) concluded that their data established a link between PML and p53 and indicated that integrity of the PML bodies is required for p53 acetylation and senescence upon oncogene expression.
Khan et al. (2001) showed that PML interacts with multiple corepressors (SKI (164780), NCOR, and Sin3A (607776)) and histone deacetylase-1 (HDAC1; 601241), and that this interaction is required for transcriptional repression mediated by the tumor suppressor MAD (600021). PML-RARA has the 2 corepressor-interacting sites and inhibits MAD-mediated repression, suggesting that aberrant binding of PML-RARA to the corepressor complexes may lead to abrogation of the corepressor function. The authors suggested that these mechanisms may contribute to events leading to leukemogenesis.
Turelli et al. (2001) showed that incoming retroviral preintegration complexes trigger the exportin (602559)-mediated cytoplasmic export of the SWI/SNF component INI1 (601607) and of the nuclear body constituent PML. They further showed that the human immunodeficiency virus (HIV) genome associates with these proteins before nuclear migration. In the presence of arsenic, PML was sequestered in the nucleus, and the efficiency of HIV-mediated transduction was markedly increased. These results unveiled an unsuspected cellular response that interferes with the early steps of HIV replication.
Yang et al. (2002) determined that PML and checkpoint kinase-2 (CHEK2; 604373) mediated p53 (191170)-independent apoptosis following gamma irradiation of several human cell lines. Endogenous CHEK2 bound PML within PML nuclear bodies. Following gamma irradiation, CHEK2 phosphorylated PML on ser117, causing dissociation of the 2 proteins. Apoptosis through this mechanism also required ATM (208900). Yang et al. (2002) concluded that this pathway to gamma irradiation-induced apoptosis utilizes ATM, CHEK2, and PML. Overexpression of PML alone caused apoptosis in U937 myeloid cells.
Lin et al. (2004) demonstrated that cytoplasmic PML is an essential modulator of TGF-beta signaling. Primary cells from Pml-null mice are resistant to TGF-beta-dependent growth arrest, induction of cellular senescence, and apoptosis. These cells also have impaired phosphorylation and nuclear translocation of the TGF-beta signaling proteins Smad2 (601366) and Smad3 (603109), as well as impaired induction of TGF-beta target genes. Expression of cytoplasmic Pml is induced by TGF-beta. Furthermore, cytoplasmic Pml physically interacts with Smad2, Smad3, and SMAD anchor for receptor activation (SARA; 603755), and is required for association of Smad2 and Smad3 with Sara and for the accumulation of Sara and TGF-beta receptor (see 190181) in the early endosome. The PML-RAR-alpha oncoprotein of acute promyelocytic leukemia can antagonize cytoplasmic PML function, and acute promyelocytic leukemia cells have defects in TGF-beta signaling similar to those observed in Pml-null cells. Lin et al. (2004) concluded that their findings identified cytoplasmic PML as a critical TGF-beta receptor and further implicated deregulated TGF-beta signaling in cancer pathogenesis.
Trotman et al. (2006) demonstrated that the PML tumor suppressor prevents cancer by inactivating phosphorylated AKT (164730) inside the nucleus. They found in a mouse model that Pml loss markedly accelerated tumor onset, incidence, and progression in Pten (601728) heterozygous mutants, and led to female sterility with features that recapitulate the phenotype of Foxo3a knockout mice. Trotman et al. (2006) showed that PML deficiency on its own leads to tumorigenesis in the prostate, a tissue that is exquisitely sensitive to phosphorylated AKT levels, and demonstrated that PML specifically recruits the AKT phosphatase PP2a (see 603113) as well phosphorylated AKT into PML nuclear bodies. Notably, Trotman et al. (2006) found that PML-null cells are impaired in PP2a phosphatase activity towards AKT, and thus accumulate nuclear phosphorylated AKT. As a consequence, the progressive reduction in PML dose leads to inactivation of FOXO3A-mediated transcription of proapoptotic BIM (603827) and the cell cycle inhibitor p27(KIP1) (600778). Trotman et al. (2006) concluded that their results demonstrate that PML orchestrates a nuclear tumor suppressor network for inactivation of nuclear phosphorylated AKT, and thus highlight the importance of AKT compartmentalization in human cancer pathogenesis and treatment.
Bernardi et al. (2006) identified PML as a critical inhibitor of neoangiogenesis (the formation of new blood vessels) in vivo, in both ischemic and neoplastic conditions, through the control of protein translation. Bernardi et al. (2006) demonstrated that in hypoxic conditions PML acts as a negative regulator of the synthesis rate of hypoxia-inducible factor 1-alpha (HIF1A; 603348) by repressing MTOR (601231). PML physically interacts with MTOR and negatively regulates its association with the small GTPase RHEB (601293) by favoring MTOR nuclear accumulation. Notably, PML-null cells and tumors display higher sensitivity both in vitro and in vivo to growth inhibition by rapamycin, and lack of PML inversely correlates with phosphorylation of ribosomal protein S6 (180460) and tumor angiogenesis in mouse and human tumors. Thus, Bernardi et al. (2006) concluded that their findings identified PML as a novel suppressor of mTOR and neoangiogenesis.
By yeast 2-hybrid analysis of a human fetal brain cDNA library, followed by coimmunoprecipitation analysis, Kunapuli et al. (2006) found that ZNF198 (ZMYM2; 602221) was covalently modified by SUMO1 (601912). Confocal microscopy showed that a proportion of ZNF198 colocalized with SUMO1 and PML in PML nuclear bodies, and coimmunoprecipitation analysis revealed that all 3 proteins resided in a protein complex. Mutation of the SUMO1-binding site of ZNF198 resulted in degradation of ZNF198, nuclear dispersal of PML, and loss of punctate PML nuclear bodies. Kunapuli et al. (2006) found that the MDA-MB-157 breast cancer cell line, which has a deletion in chromosome 13q11 encompassing the ZNF198 gene, lacked PML nuclear bodies, although PML protein levels appeared normal. The fusion protein ZNF198/FGFR1 (136350), which occurs in atypical myeloproliferative disease (613523) and lacks the SUMO1-binding site of ZNF198, could dimerize with wildtype ZNF198 and disrupt its function. Expression of ZNF198/FGFR1 disrupted PML sumoylation and nuclear body formation and resulted in cytoplasmic localization of SUMO1. Kunapuli et al. (2006) concluded that sumoylation of ZNF198 is required for PML nuclear body formation.
Using wildtype and Irf8 (601565) -/- mice, Dror et al. (2007) showed that Irf8 was essential for induced expression of Pml in macrophages and for constitutive expression of Pml in hematopoietic tissues. The authors identified PML-I as the major PML splice variant induced in IFN-gamma (IFNG; 147570)- and lipopolysaccharide-activated human U937 promyelocytic cell line, indicating that IRF8 mediates PML-I expression. Regulation of Pml-I expression by Irf8 occurred through a specific ISRE located within the Pml promoter and through cooperative interaction with transcription factors Irf1 (147575) and Pu.1 (SPI1; 165170) in mouse macrophages. Irf8 was not only essential for the Ifn-gamma-induced expression of Pml in activated mouse macrophages, but also for formation of Pml nuclear bodies.
Ito et al. (2008) showed that PML is critical in the maintenance of quiescent leukemia-initiating cells and normal hematopoietic stem cells. They suggested that targeting PML may be an effective treatment for prevention of relapse in CML (608232).
Song et al. (2008) found that PTEN was aberrantly localized in APL in which PML function was disrupted by the PML-RARA fusion oncoprotein. Treatment with drugs that triggered PML-RARA degradation restored nuclear PTEN. PML opposed the activity of HAUSP (USP7; 602519) towards PTEN through a mechanism involving DAXX (603186). Confocal microscopy and immunohistochemistry demonstrated that HAUSP was overexpressed in prostate cancer and that levels of HAUSP directly correlated with tumor aggressiveness and with PTEN nuclear exclusion. Song et al. (2008) concluded that a PML-HAUSP network controls PTEN deubiquitinylation and subcellular localization, which is perturbed in human cancers.
Arsenic, an ancient drug used in traditional Chinese medicine, has attracted worldwide interest because it shows substantial anticancer activity in patients with acute promyelocytic leukemia (APL). Arsenic trioxide exerts its therapeutic effect by promoting degradation of PML-RARA. PML and PML-RARA degradation is triggered by their sumoylation, but the mechanism by which arsenic trioxide induces this posttranslational modification was unclear. Zhang et al. (2010) showed that arsenic binds directly to cysteine residues in zinc fingers located within the RBCC domain of PML-RARA and PML. Arsenic binding induces PML oligomerization, which increases its interaction with the small ubiquitin-like protein modifier (SUMO)-conjugating enzyme UBC9 (601661), resulting in enhanced sumoylation and degradation. Zhang et al. (2010) concluded that the identification of PML as a direct target of arsenic trioxide provides insights into the drug's mechanism of action and its specificity for APL.
In mouse embryonic fibroblasts, Giorgi et al. (2010) found that extranuclear Pml was specifically enriched at the endoplasmic reticulum (ER) and at the mitochondria-associated membranes, signaling domains involved in ER-to-mitochondria calcium ion transport and in induction of apoptosis. They found Pml in complexes of large molecular size with the inositol 1,4,5-triphosphate receptor (IP3R; 147265), protein kinase Akt (164730), and protein phosphatase 2a (176915). Pml was essential for Akt- and PP2a-dependent modulation of Ip3r phosphorylation and in turn for Ip3r-mediated calcium ion release from the endoplasmic reticulum. Giorgi et al. (2010) concluded that their findings provided a mechanistic explanation for the pleiotropic role of Pml in apoptosis.
Reviews of PML Function
Bernardi and Pandolfi (2007) reviewed the structure, dynamics, and functions of PML-NBs.
Salomoni et al. (2008) reviewed the role of PML in tumor suppression.
PML/RARA Fusion Protein
For information on the generation of PML/RARA fusion genes through translocations associated with APL, see CYTOGENETICS.
Grignani et al. (1993) expressed the PML-RARA protein in U937 myeloid precursor cells and showed that they lost the capacity to differentiate under the action of stimuli such as vitamin D3 and transforming growth factor beta-1 (TGFB1; 190180), acquired enhanced sensitivity to retinoic acid, and exhibited a higher growth rate consequent to diminished apoptotic cell death. These results provided evidence of biologic activity of the fusion protein and recapitulated critical features of the promyelocytic leukemia phenotype.
Lin et al. (1998) reported that the association of PLZF-RAR-alpha (see 176797) and PML-RAR-alpha with the histone deacetylase complex (see 605164) helps to determine both the development of APL and the ability of patients to respond to retinoids. Consistent with these observations, inhibitors of histone deacetylase dramatically potentiate retinoid-induced differentiation of retinoic acid-sensitive, and restore retinoid responses of retinoic acid-resistant, APL cell lines. Lin et al. (1998) concluded that oncogenic retinoic acid receptors mediate leukemogenesis through aberrant chromatin acetylation, and that pharmacologic manipulation of nuclear receptor cofactors may be a useful approach in the treatment of human disease.
Grignani et al. (1998) demonstrated that both PML-RAR-alpha and PLZF-RAR-alpha fusion proteins recruit the nuclear corepressor (NCOR; see 600849)-histone deacetylase complex through the RAR-alpha CoR box. PLZF-RAR-alpha contains a second, retinoic acid-resistant binding site in the PLZF amino-terminal region. High doses of retinoic acid release histone deacetylase activity from PML-RAR-alpha, but not from PLZF-RAR-alpha. Mutation of the NCOR binding site abolishes the ability of PML-RAR-alpha to block differentiation, whereas inhibition of histone deacetylase activity switches the transcriptional and biologic effects of PLZF-RAR-alpha from being an inhibitor to an activator of the retinoic acid signaling pathway. Therefore, Grignani et al. (1998) concluded that recruitment of histone deacetylase is crucial to the transforming potential of APL fusion proteins, and the different effects of retinoic acid on the stability of the PML-RAR-alpha and PLZF-RAR-alpha corepressor complexes determines the differential response of APLs to retinoic acid.
RAR and acute myeloid leukemia-1 (AML1; 151385) transcription factors are found in leukemias as fusion proteins with PML and ETO (CBFA2T1; 133435), respectively. Association of PML-RAR and AML1-ETO with the NCOR-histone deacetylase complex is required to block hematopoietic differentiation. Minucci et al. (2000) showed that PML-RAR and AML1-ETO exist in vivo within high molecular weight nuclear complexes, reflecting their oligomeric state. Oligomerization requires PML or ETO coiled-coil regions and is responsible for abnormal recruitment of NCOR, transcriptional repression, and impaired differentiation of primary hematopoietic precursors. Fusion of RAR to a heterologous oligomerization domain recapitulated the properties of PML-RAR, indicating that oligomerization per se is sufficient to achieve transforming potential. These results showed that oligomerization of a transcription factor, imposing an altered interaction with transcriptional coregulators, represents a novel mechanism of oncogenic activation.
The recruitment of the nuclear receptor corepressor SMRT (NCOR2; 600848) and subsequent repression of retinoid target genes is critical for the oncogenic function of PML-RARA. Lin and Evans (2000) showed that the ability of PML-RARA to form homodimers is both necessary and sufficient for its increased binding efficiency to corepressor and its inhibitory effects on hormonal responses in myeloid differentiation. Furthermore, the authors found that altered stoichiometric interaction of SMRT with PML-RARA homodimers may underlie these processes. An RXR mutant lacking transactivation function AF2 recapitulated many biochemical and functional properties of PML-RARA. Taken together, these results indicated that altered dimerization of a transcription factor can be directly linked to cellular transformation, and they implicated dimerization interfaces of oncogenes as potential drug targets.
Pandolfi (2001) reviewed the roles of the RARA and PML genes in the pathogenesis of APL and discussed the multiple oncogenic activities of PML-RARA.
Di Croce et al. (2002) demonstrated that PML-RARA fusion protein induces gene hypermethylation and silencing by recruiting DNA methyltransferases to target promoters and that hypermethylation contributes to its leukemogenic potential. Retinoic acid treatment induces promoter demethylation, gene reexpression, and reversion of the transformed phenotype. Di Croce et al. (2002) concluded that their results establish a mechanistic link between genetic and epigenetic changes during transformation and suggest that hypermethylation contributes to the early steps of carcinogenesis.
The fusion protein PML-RARA initiates APL when expressed in the early myeloid compartment of transgenic mice. Lane and Ley (2003) found that PML-RARA was cleaved in several positions by a neutral serine protease in a human myeloid cell line; purification revealed that the protease was neutrophil elastase (ELA2; 130130). Immunofluorescence localization studies suggested that cleavage of PML-RARA must have occurred within the cell, perhaps within the nucleus. The functional importance of ELA2 for APL development was assessed in Ela2-deficient mice. More than 90% of bone marrow PML-RARA-cleaving activity was lost in the absence of Ela2, and Ela2-deficient animals, but not cathepsin G (116830)-deficient animals, were protected from APL development. The authors determined that primary mouse and human APL cells also contained ELA2-dependent PML-RARA-cleaving activity. Lane and Ley (2003) concluded that, since ELA2 is maximally produced in promyelocytes, it may play a role in APL pathogenesis by facilitating the leukemogenic potential of PML-RARA.
Villa et al. (2006) found that MBD1 (156535) cooperated with PML-RARA in transcriptional repression and cellular transformation in human cell lines. PML-RARA recruited MBD1 to its target promoter through an HDAC3 (605166)-mediated mechanism. Binding of HDAC3 and MBD1 was not confined to the target promoter, but was instead spread over the locus. Knockdown of HDAC3 expression by RNA interference in acute promyelocytic leukemia cells alleviated PML-RARA-induced promoter silencing. Furthermore, retroviral expression of dominant-negative mutants of MBD1 in human hematopoietic precursors interfered with PML-RARA-induced repression and restored cell differentiation. Villa et al. (2006) concluded that PML-RARA recruits an HDAC3-MBD1 complex to target promoters to establish and maintain chromatin silencing.
PML/RARA Fusion Gene
In the process of analyzing the RARA gene in the t(15;17)(q22;q11.2-q12) translocation specifically associated with acute promyelocytic leukemia (APL), de The et al. (1990) identified a novel gene on chromosome 15 involved with the RARA gene in formation of a fusion product. This gene, which they called MYL, was transcribed in the same direction as RARA on the translocated chromosome. In the chimeric gene, the promoter and first exon of the RARA gene were replaced by part of the MYL gene. De The et al. (1990) established that the translocation chromosome generates an MYL-RARA chimeric transcript. The findings strongly implicated RARA in leukemogenesis. The possibility was raised that the altered retinoic acid receptor behaves as a dominant-negative mutant that blocks the expression of retinoic acid target genes involved in granulocytic differentiation. In a later report, de The et al. (1991) changed the name of the gene from MYL to PML. The PML-RARA mRNA encoded a predicted 106-kD chimeric protein containing most of the PML sequences fused to a large part of the RARA gene, including its DNA- and hormone-binding domains.
Goddard et al. (1991) determined that the PML breakpoints were clustered in 2 regions on either side of an alternatively spliced exon. Although leukemic cells with translocations characteristically expressed only 1 fusion product, both PML-RARA (on the 15q+ derivative chromosome) and RARA-PML (on the 17q- derivative) were transcribed. The contribution of PML to the oncogenicity of the fusion products was demonstrated by the following: no mutations affecting RARA alone were observed in 20 APLs analyzed; 2 APLs cytogenetically lacking t(15;17) chromosomes were found to have rearrangements of both PML and RARA; and PML but not RARA was molecularly rearranged in a variant APL translocation in which chromosome 15 had been translocated to another chromosome with no visible involvement of chromosome 17.
Tong et al. (1992) found that in 20 of 22 patients with a detectable MYL rearrangement the breakpoints were clustered within a 4.4-kb segment, which they designated MYL(bcr). The 2 remaining patients exhibited a more 5-prime rearrangement at about 10-kb upstream of the MYL(bcr) region, indicating the lack of at least one MYL gene exon in the resulting MYL-RARA fusion gene.
Cleary (1991) pointed out that detection of the PML-RARA fusion links a specific molecular defect in neoplasia with a characteristic biologic and clinical response to pharmacologic therapy. It is a useful marker for the diagnosis of APL and for the identification of patients who may benefit from retinoid treatment.
PML, the gene involved in the breakpoint on chromosome 15, is a putative transcription factor: it contains a cysteine-rich motif that resembles a zinc finger DNA-binding domain common to several classes of transcriptional factors. Two fusion genes, PML-RARA and RARA-PML, are formed as a result of the characteristic translocation in APL. Heterogeneity of the chromosome 15 breakpoints accounts for the diverse architecture of the PML-RARA mRNAs isolated from different APL patients, and alternative splicing of PML exons gives rise to multiple isoforms of the PML-RARA mRNAs even within a single patient. Alcalay et al. (1992) investigated the organization and expression pattern of the RARA/PML gene in a series of APL patients. A RARA-PML transcript was present in most but not all APL patients. Among 70 patients with APL, Diverio et al. (1992) found an abnormality in intron 2 of the RARA gene in all cases, with clustering of rearrangements within the 20-kb intronic region separating exons 2 and 3. A curious difference was found in the location of breakpoints in males and females: breakpoints at the 5-prime end of intron 2 of the RARA gene occurred in females and 3-prime breakpoints predominated in males.
Stock et al. (2000) pointed out that breakpoints in chromosomes 15 and 17 leading to the translocation associated with APL had been described as located between 15q22 and 15q26, and between 17q11 and 17q25. Most studies using FISH had indicated the chromosome 15 breakpoint to be in 15q22. Stock et al. (2000) used a combination of G-banding, FISH, and chromosome microdissection/reverse in situ hybridization to map the breakpoints precisely to 15q24 and 17q21.1.
Zaccaria et al. (2002) studied a rare example of cryptic translocation causing APL. Conventional cytogenetics showed a normal karyotype; PCR showed a typical PML-RARA rearrangement in exon 1. FISH analysis revealed that a submicroscopic part of chromosome 15 had been inserted into 17q. Zaccaria et al. (2002) reviewed other cases of cryptic translocation; their report appeared to be the first in which both pairs of chromosomes 15 and 17 were cytogenetically normal and a PML-RARA fusion gene, discovered after FISH analysis, was located on chromosome 17. A poor response to ATRA therapy was postulated to have a relationship to the atypical translocation.
Abreu e Lima et al. (2005) described a 47-year-old woman with acute myeloid leukemia who had simultaneous expression of the PML/RARA and the AML1/ETO (133435) fusion genes. Despite prolonged use of therapeutic doses of ATRA plus chemotherapy, the patient did not achieve remission, in contrast to the experience of most patients with such fusion genes. Conventional cytogenetics in this case showed the presence of only the t(8;21) translocation. In previous reports of coexpression of these 2 fusion genes there was evidence of the presence of 2 or 3 distinct leukemic clones harboring either or both chromosomal translocations.
Brown et al. (1997) established a transgenic mouse model that documented the ability of the chimeric PML-RARA gene to initiate leukemogenesis. The mice developed 2 currently unrelated abnormalities. The first was a severe papillomatosis of the skin; the second was a disturbance of hematopoiesis that presented as a partial block of differentiation in the neutrophil lineage of the transgenic mice and then progressed at low frequency to overt APL. The leukemia appeared to be a faithful reproduction of the human disease, including a therapeutic response to retinoic acid that reflected differentiation of the leukemic cells. Both the preleukemic state and the overt leukemia could be transplanted into nontransgenic hosts. Brown et al. (1997) commented that the model should be useful for exploring the pathogenesis and treatment of APL.
From studies in mice with disruption of the Pml gene, Wang et al. (1998) demonstrated that normally, PML regulates hemopoietic differentiation and controls cell growth and tumorigenesis. PML function is essential for the tumor-growth-suppressive activity of retinoic acid (RA) and for its ability to induce terminal myeloid differentiation of precursor cells. PML was needed for the RA-dependent transactivation of the p21(Waf1/Cip1) gene (116899), which regulates cell cycle progression and cellular differentiation. These results provided a framework for understanding the molecular pathogenesis of APL. Whereas APL might result from the functional interference of PML/RARA with 2 independent pathways, PML and RXR/RAR, Wang et al. (1998) showed that these proteins act, at least in part, in the same pathway. Thus, by simultaneously interacting with RXR and PML, the fusion gene product may inactivate this pathway at multiple levels, leading to the proliferative advantage and the block of hemopoietic differentiation that characterize APL.
David et al. (1997) generated an inducible line of transgenic mice in which the expression of PML-RARA is driven by the metallothionein promoter. After 5 days zinc stimulation, 27 of 54 mice developed hepatic preneoplasia and neoplasia including foci of basophilic hepatocytes, dysplasia, and carcinoma, with a significantly higher incidence of lesions in females than in males. The rapid onset of liver pathologies was dependent on overexpression of the transgene, since it was not detected in noninduced transgenic animals of the same age. The PML-RARA protein was always present in altered tissues at much higher levels than in the surrounding normal liver tissues. In addition, overexpression of PML-RARA resulted in a strong proliferative response in the hepatocytes. David et al. (1997) concluded that overexpression of PML-RARA deregulates subproliferation and can induce tumorigenic changes in vivo.
In an animal model of acute promyelocytic leukemia, Padua et al. (2003) developed a DNA-based vaccine by fusing the human PML-RARA oncogene to tetanus fragment C (FrC) sequences. Padua et al. (2003) showed for the first time that a DNA vaccine specifically targeted to an oncoprotein can have a pronounced effect on survival, both alone and in combination with all-trans retinoic acid (ATRA). The survival advantage was concomitant with time-dependent antibody production and an increase in interferon-gamma. Padua et al. (2003) also showed that ATRA therapy on its own triggered an immune response in this model. When DNA vaccination and conventional ATRA therapy were combined, they induced protective immune responses against leukemia progression in mice. Padua et al. (2003) concluded that this may provide a new approach to improve clinical outcome in human leukemia.
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