Molecular biology of acute promyelocytic leukemia
Authors
Wendy Stock, MD
Michael J Thirman, MD Section Editor
Richard A Larson, MD Deputy Editor
Rebecca F Connor, MD
Last literature review version 16.3: September 2008 | This topic last updated: June 9, 2008 (More)
INTRODUCTION — The cytogenetic hallmark of acute promyelocytic leukemia (APL), FAB-M3 in the French-American-British classification of acute myeloid leukemia (AML), is a translocation involving the retinoic acid receptor-alpha (RAR-alpha, RARa) locus on chromosome 17 [1] . The vast majority of these cases contain t(15;17)(q22;q11.12), although several variant translocations involving RARa have been identified, including t(11;17) and t(5;17) [2-4] . (See "Variant translocations" below). Distinguishing between these translocations is important because patients with the variant translocation t(11;17)(q23;q11.12) are almost invariably resistant to ATRA [2,3,5] . (See "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults").
The molecular biology of APL will be discussed here. The molecular biology of acute myeloid leukemias other than APL and of ALL are discussed separately. (See "Pathobiology of acute myeloid leukemia" and see "Cytogenetics in acute lymphoblastic leukemia").
RETINOIC ACID AND THE RETINOIC ACID RECEPTOR — Retinoic acid is a critical ligand in the differentiation pathway of multiple tissues, mediated through binding to a retinoic acid receptor (RAR). RARs belong to the nuclear steroid/thyroid hormone receptor superfamily, and possess a modular structure with discrete ligand binding and DNA binding domains. Of the three isoforms of RARs, RARalpha (RARa) is expressed primarily in hematopoietic cells.
RARa is a member of a family of retinoid-binding transcription factors (including RXR) that regulate gene expression. RARa contains a series of discrete functional domains, including an amino terminal transcriptional activation domain, followed by DNA-binding, dimerization, and retinoid-binding domains. RARa heterodimerizes with retinoid X receptor (RXR), and binds to retinoic acid responsive elements to regulate transcription of target genes [5] .
In the absence of retinoic acid, RARa/RXR-alpha heterodimers interact with N-CoR (nuclear corepressor), a ubiquitous nuclear protein which mediates transcriptional repression [2,6] . Retinoic acid dissociates N-CoR from RARa/RXR-alpha, resulting in relief from transcriptional repression, presumably activating genes that lead to terminal differentiation of promyelocytes (show bone marrow 1A-1B) [6,7] .
The capacity of retinoids to induce myeloid differentiation was recognized prior to the identification of the involvement of RARa in APL. Retinoic acid had been shown to enhance the growth of normal myeloid progenitors, to induce differentiation of the HL-60 promyelocytic cell line, and to induce terminal differentiation of primary human APL cells cultured in vitro [8-10] . Subsequently, the use of all-trans retinoic acid (ATRA) was found to induce complete remissions in patients with APL. (See "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults", section on Initial treatment).
Rather than inducing cell death from cytotoxicity, ATRA induces differentiation of the malignant promyelocytic clone, an effect which can be observed in vitro and in vivo [11-13] . The effect in retinoic acid-sensitive NB4 cells in vivo is complex [14] , with ATRA modulating 169 genes in one study [12] . Although complete remission can be obtained with ATRA alone, most patients will ultimately relapse without additional cytotoxic chemotherapy. The basis for development of ATRA resistance remains unclear, but this phenomenon suggests that additional genetic events might occur in APL cells that confer resistance. The use of arsenic trioxide has also been shown to induce remissions in APL, possibly by inducing the degradation of PML/RARa. (See "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults", section on Arsenic trioxide).
T(15;17) THE USUAL TRANSLOCATION IN APL — The leukemic cells of approximately 92 percent of patients with APL have the balanced translocation t(15;17)(q22;q11.12) involving the retinoic acid receptor-alpha (RAR-alpha, RARa) gene on chromosome 17 and the PML gene on chromosome 15 [3,5] . An additional 5 percent do not have the classic t(15;17), but have the PML/RARalpha fusion gene, due to insertions or other complex chromosomal rearrangements [15] .
The PML gene — The ProMyelocytic Leukemia (PML) gene was first identified through its involvement with RARa in t(15;17) [16,17] . It is expressed ubiquitously, and multiple alternative splice variants have been isolated. The normal function of PML is not known, but overexpression of PML inhibits growth in cell lines, perhaps through the interferon-gamma signaling pathway [18] . Several studies have suggested the following properties for the gene [19-21] : It is critical for the proper localization of all other ND10-associated proteins under physiological conditions It encodes a growth- and tumour-suppresor protein that is essential for several apoptotic signals It acts as a transcriptional co-activator with p53, the tumor suppressor gene
The product of the PML gene is a nuclear protein that contains motifs suggestive of a role in control of RNA transcription, including two putative amino terminal DNA-binding domains and a potential dimerization domain. It is normally expressed in myeloid progenitors, and has been shown to localize to a discrete subnuclear compartment of unknown function, referred to as the nuclear body [22] .
The nuclear body is a novel nuclear structure referred to by several names, including PODs (PML oncogenic domains), or ND10 (nuclear domain 10) [22,23] . In APL cells, the integrity of the nuclear body is disrupted, and a microspeckled distribution of PML/RARa is observed. Treatment of APL cells with ATRA causes the nuclear bodies to be regenerated with proper relocalization of PML. Arsenic trioxide has also been found to target PML and PML/RARa to nuclear bodies and to induce their degradation [24] . Thus, restoration of nuclear body structures by either ATRA or arsenic trioxide correlates with the ability of these agents to induce remission of APL.
The fusion genes of t(15;17) — Two novel fusion genes are formed as a result of the t(15;17): a PML/RARa gene on the der(15) chromosome and an RARa/PML gene on the der(17) [16,17] . Whereas the PML/RARa fusion gene is found consistently in all cases of t(15;17), the reciprocal RARa/PML fusion can be detected in only 80 percent of cases [25] , due in some cases to loss of the der(17) chromosome. Although this suggests that the RARa/PML fusion may not be essential in the pathogenesis of APL, its expression has been postulated to represent a potential second genetic event contributing to the leukemic phenotype.
The resulting fusion gene on der(15) encodes a fusion protein in which the DNA-binding and dimerization domains of PML are fused to the DNA-binding and C-terminal portions of RAR-alpha, including the retinoid binding site. Breakpoints in RARa typically occur within intron 2, whereas breakpoints in PML are more heterogeneous, occurring within intron 3, intron 6, or exon 6, producing what has been called short, long, and variable forms [26,27] . The three different isoforms have somewhat different clinical characteristics; lack of sufficient numbers of patients with the less common variable form has made it difficult to determine whether the three isoforms have similar clinical outcomes [26-28] .
Mechanism of action of PML/RARa — The PML/RARa protein functions as an aberrant retinoid receptor that possesses altered DNA binding and transcriptional regulatory properties [29,30] . PML/RARa can heterodimerize with RXR and bind to retinoic acid responsive elements in target genes. Expression of PML/RARa blocks retinoic acid induced myeloid differentiation [31] .
In addition, PML/RARa can block RARa mediated transactivation in a dominant negative manner. This dominant negative effect on normal RARa mediated functions is supported by experiments where a dominant negative mutation of RARa was introduced into a murine hematopoietic cell line [32] . A block in differentiation along the neutrophil and monocytic lineages was observed, and a switch to the development of mast cells and basophils occurred.
Experiments in transgenic mice demonstrated that expression of PML/RARa in immature myeloid cells resulted in the development of a leukemia with promyelocytic features, thereby demonstrating the leukemogenic potential of the fusion protein [33] . Expression of a PML/RARa variant that is unable to activate transcription in response to retinoic acid also leads to leukemia; however, the leukemia does not differentiate in response to retinoic acid [34] . Several groups have generated transgenic mice expressing PML/RARa under the control of various myeloid-specific promoters. The phenotype in these mice depended on the stage of myeloid differentiation where the transgene was expressed: In mice with the transgene expressed under the control of the human MRP8 promoter, which drives expression in early myeloid progenitors as well as in mature neutrophils and monocytes, neutrophil numbers were normal, but differentiation was impaired. Approximately 30 percent developed acute leukemia with a latency of three to nine months; remission of the leukemia could be induced by ATRA [33] . Two groups have generated transgenic mice expressing PML/RARa under the control of the human cathepsin G promoter, which drives expression in promonocytes and promyelocytes. These mice develop elevated numbers of immature myeloid cells in the bone marrow and peripheral blood. Approximately 10 to 30 percent develop leukemia with a latency of 12 to 14 months [35,36] . Treatment of these mice with ATRA caused apoptosis of myeloid precursors rather than differentiation. Transgenic mice expressing PML-RARa under the control of the CD11b promoter have also been generated [37] . This promoter drives expression in later stages of myeloid differentiation. These mice do not develop leukemia and have normal numbers and maturation of myeloid cells. However, the ability of these mice to regenerate granulocytes following sublethal irradiation was impaired.
Comparison of the phenotypes observed in the different transgenic mice reveals that the timing of PML-RARa expression during myeloid differentiation is a critical determinant in the development of leukemia. In addition, the relatively low frequency and long latency period for development of leukemia imply that genetic events in addition to the expression of PML-RARa are necessary in order for APL to occur [38,39] .
The precise way in which the fusion protein functions as an oncoprotein is incompletely understood. The two isoforms, PML/RARa and RARa/PML, have only subtle differences in function [40] . PML/RARa shows reduced sensitivity to retinoic acid in terms of dissociation of N-CoR [6] . This could lead to persistent transcriptional repression, thereby preventing differentiation of promyelocytes. Pharmacologic concentrations of retinoic acid, as used in the treatment of APL, result in dissociation of N-CoR, presumably permitting differentiation of the leukemic cells [6] .
The binding of the protein product of PML/RARa is thought to repress gene transcription through epigenomic changes including histone deacetylation or methylation [41] . A mechanism which includes the recruitment of a histone deacetylase may have therapeutic implications because in vitro studies have shown that resistance to all-trans retinoic acid can be overcome by the addition of a histone deacetylase inhibitor [42,43] . In addition, case reports and small trials have reported clinical responses to histone deacetylase inhibitors [44,45] . (See "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults" section on Inhibition of histone deacetylase).
PML/RARa also may prolong the survival of the leukemic cells, perhaps in part by leading to downregulation of tumor necrosis factor-alpha (TNFa) receptors, thereby minimizing TNFa-induced apoptosis [46] . On the hand, PML/RARa in the presence of retinoic acid induces apoptosis in association with reduced levels of BCL-2 which normally protects against apoptosis [40] .
In support of this hypothesis are results obtained with mouse [47] and human [48] multipotent hematopoietic progenitor cells/stem cells (HPC/HSC) transfected in vitro with a retroviral vector containing PML/RARa cDNA. Expression of the PML/RARa fusion protein in human cells dictated the APL phenotype through the following effects [48] : Rapid induction of human HPC/HSC differentiation to the promyelocytic stage Maturation arrest at the promyelocytic stage, which was abolished by retinoic acid Reprogramming of HPC commitment to preferential granulopoietic differentiation irrespective of the hematopoietic growth factor (HGF)
stimulus Protection of HPC from apoptosis induced by HGF deprivation.
VARIANT TRANSLOCATIONS — A number of variant translocations have been described in APL, t(11;17)(q23;q11.12), t(5;17)(q35;q11.12), and t(11;17)(q13;q11.12).
PLZF/RARa and t(11;17) — A variant translocation t(11;17)(q23;q11.12) has been described in approximately one percent of patients with APL [15,49] . In these tumors, the 3' end of the RARa gene is fused to the 5' end of a gene called PLZF (promyelocytic leukemia zinc finger), which encodes a polypeptide containing nine zinc fingers, a motif frequently found in transcription factors. PLZF is expressed in myeloid but not lymphoid lineages, and its expression has been found to be downregulated during differentiation. Unlike PML, PLZF is not a component of nuclear bodies, but is localized in smaller, more numerous nuclear subdomains.
The PLZF/RARa fusion gene is predicted to encode a protein consisting of the amino terminal portion of PLZF, including several zinc fingers, and the same carboxy terminal portion of RARa that is fused to PML in cells having t(15;17). The PLZF/RARa fusion protein antagonizes the normal function of RARa/RXR-alpha heterodimers, suggesting that it behaves as a dominant negative mutant [50] .
Although the number of cases studied is small, APL with t(11;17)(q23;q11.12) is usually refractory to therapy with retinoids, in contrast to the great majority of APL cases with the more common t(15;17) [2,51] . As noted above, PML/RARa in t(15;17) shows reduced sensitivity to retinoic acid, but this can be overcome by pharmacological concentrations of retinoic acid. In contrast, pharmacological concentrations of retinoic acid do not induce dissociation of N-CoR from PLZF/RARa, leading to persistent transcription repression and prevention of differentiation [6,52] .
NPM/RARa and t(5;17) — A rare (less than 0.5 percent) variant translocation in APL has been described, t(5;17)(q35;q11.12), in which the nucleophosmin (NPM) gene was fused to RARa [15,53] . NPM is a nucleolar phosphoprotein that is involved in ribosomal ribonucleoprotein processing and transport. NPM is also involved in the t(2;5)(p23;q35) in anaplastic large cell lymphoma, where it fuses to the ALK gene. In addition, NPM has been found to fuse to the MLF1 gene in t(3;5)(q25.1;q35) in AML. Patients with this translocation are responsive to ATRA therapy [5] .
NuMA/RARa and t(11;17) — In the translocation t(11;17)(q13;q11.12), the Nuclear matrix-mitotic apparatus protein gene (NuMA) is fused with RARa [5] . Unlike t(11;17)(q23;q11.12), this variant appears responsive to ATRA [54] .
STAT5b/RARa and interstitial chromosome 17 deletion — A rare fusion between STAT5b (signal transducer and activator of transcription 5b) and RARa was found in a patient with an interstitial chromosome 17 deletion and an ATRA-resistant form of APL [55-57] .
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