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Molecular biology of acute promyelocytic leukemia

Molecular biology of acute promyelocytic leukemia
Literature review current through: Jan 2024.
This topic last updated: Feb 04, 2022.

INTRODUCTION — Acute myeloid leukemia (AML) refers to a group of hematopoietic neoplasms involving cells committed to the myeloid lineage. Acute promyelocytic leukemia (APL) is a biologically and clinically distinct variant of AML. In the World Health Organization classification system, APL is classified as acute promyelocytic leukemia with PML-RARA; it was previously classified as AML-M3 in the older French-American-British (FAB) classification system [1,2]. (See "Acute myeloid leukemia: Classification".)

The cytogenetic hallmark of APL is a translocation involving RARA, the retinoic acid receptor alpha locus on chromosome 17 [3]. The vast majority of cases of APL contain t(15;17)(q24.1;q21.1). However, several variant translocations involving RARA have been identified, including t(11;17) and t(5;17) [4-6], and distinguishing between these translocations is important because patients with the variant translocation t(11;17) are almost invariably resistant to all-trans retinoic acid (ATRA) [4,5,7]. (See "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults" and "Initial treatment 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 is discussed separately. (See "Acute myeloid leukemia: Pathogenesis" and "Classification, cytogenetics, and molecular genetics of acute lymphoblastic leukemia/lymphoma" and "Acute myeloid leukemia: Molecular genetics".)

RETINOIC ACID AND THE RETINOIC ACID RECEPTOR — Retinoic acid (RA) is a critical ligand in the differentiation of multiple tissues, mediated through binding to a retinoic acid receptor (RAR). RARs belong to the nuclear steroid/thyroid hormone receptor superfamily. Of the three RAR isoforms, RAR alpha is expressed primarily in hematopoietic cells.

RAR alpha is a member of a family of retinoid-binding transcription factors (including RXR) that regulate gene expression. RAR alpha contains discrete functional domains, including an amino terminal transcriptional activation domain, and DNA-binding, dimerization, and retinoid-binding domains. RAR alpha heterodimerizes with retinoid X receptor (RXR), and binds to RA-responsive elements to regulate transcription of target genes [7].

In the absence of RA, heterodimers of RAR alpha/RXR alpha interact with the nuclear corepressor, N-CoR, a ubiquitous nuclear protein that mediates transcriptional repression [4,8]. RA dissociates N-CoR from the RAR alpha/RXR alpha heterodimer, relieving transcriptional repression and presumably activating genes that lead to terminal differentiation of promyelocytes (picture 1A-B) [8,9].

The capacity of retinoids to induce myeloid differentiation was recognized prior to the identification of the involvement of RAR alpha in acute promyelocytic leukemia (APL). RA 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 [10-12]. Subsequently, the use of all-trans retinoic acid (ATRA) was found to induce complete remissions in patients with APL. (See "Initial treatment of acute promyelocytic leukemia in adults".)

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 [13-15]. The effect in RA-sensitive NB4 cells in vivo is complex [16], with ATRA modulating expression of 169 genes in one study [14]. Although complete remission can be obtained with ATRA alone, most patients with APL 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/RAR alpha [17]. (See "Treatment of relapsed or refractory acute promyelocytic leukemia in adults".)

t(15;17) THE USUAL TRANSLOCATION IN APL — The leukemic cells of approximately 92 percent of patients with acute promyelocytic leukemia (APL) have the balanced translocation t(15;17)(q24.1;q21.1) involving RARA, the retinoic acid receptor alpha gene on chromosome 17 and the PML (promyelocytic leukemia) gene on chromosome 15 [5,7]. An additional 5 percent of patients do not have the classic t(15;17), but have the PML/RARA fusion gene, due to insertions or other complex chromosomal rearrangements [18].

The PML gene — The PML gene was first identified through its involvement with RARA in t(15;17) [19,20]. PML is expressed ubiquitously, and multiple alternative splice variants have been isolated. The normal function of the PML protein is not known, but overexpression of PML inhibits growth in cell lines, perhaps through the interferon gamma signaling pathway [21].

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. PML 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 (NB); the NB is also referred to as POD (PML oncogenic domain) or ND10 (nuclear domain 10) [22,23].

In APL cells, NB integrity is disrupted and a microspeckled distribution of PML/RAR alpha is observed. NB disruption may contribute to disease pathogenesis and restoration of NB formation by all-trans retinoic acid (ATRA) or arsenic trioxide (ATO) correlates with their ability to induce remission of APL [24]. In a mouse model, mutations of PML that disrupted the NB increased the frequency of leukemia development, reduced the latency period, and impaired DNA damage responses [25].

The following functional properties of the PML protein have been described [26-28]:

Localization of PML-associated proteins under physiological conditions

Growth- and tumor-suppressor functions that are essential for certain apoptotic signals

Transcriptional co-activation with the tumor suppressor p53 (encoded by the TP53 gene)

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) [19,20]. 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 [29] due, in some cases, to loss of the der(17) chromosome. Although this suggests that the RARA/PML fusion protein 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 [30,31]. 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 [30-32].

Mechanism of action of PML/RARA — The PML/RAR alpha protein functions as an aberrant retinoid receptor that possesses altered DNA binding and transcriptional regulatory properties [33,34]. PML/RAR alpha can heterodimerize with RXR and bind to retinoic acid (RA)-responsive elements in target genes. Expression of PML/RAR alpha blocks retinoic acid induced myeloid differentiation [35]. PML/RAR alpha can also block RAR alpha mediated transactivation in a dominant negative (DN) manner, as shown by experiments in which a DN mutation of RARA was introduced into a murine hematopoietic cell line; a block in differentiation along the neutrophil and monocytic lineages was observed and, instead, a switch to the development of mast cells and basophils occurred [36].

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 [37]. Expression of a PML/RARA variant that is unable to activate transcription in response to RA also leads to leukemia, but the leukemia does not differentiate in response to RA [38].

The timing of PML/RARA expression during myeloid differentiation is a critical determinant in the development of leukemia. Comparison of the phenotypes in the transgenic mice that drive expression of PML/RARA under the control of various myeloid-specific promoters at specific stages of myeloid differentiation include the following:

In mice with the PML/RARA transgene expressed under the control of the human MRP8 (myeloid related protein 8) promoter, which drives expression in early myeloid progenitors and 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 [37].

Two groups generated transgenic mice expressing PML/RARA under the control of the CTSG (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 [39,40]. Treatment of these mice with ATRA caused apoptosis of myeloid precursors rather than differentiation.

Transgenic mice expressing PML/RARA under the control of the ITGAM (integrin subunit alpha M; CD11b) promoter have also been generated [41]. 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.

Transgenic mice expressing PML-RARA in the setting of PML haploinsufficiency demonstrate a preferential expansion of PML/RAR alpha-expressing cells, suggesting that this transgene supports self-renewal [42]. This study showed that PML/RAR alpha can increase hematopoietic self-renewal without causing a myeloproliferative neoplasm in mice.

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 [43,44].

The precise way in which the fusion protein functions as an oncoprotein is incompletely understood. The two products of the t(15;17) translocation (ie, PML/RAR alpha and RAR alpha/PML) exhibit only subtle differences in function [45]. PML/RAR alpha shows reduced sensitivity to retinoic acid (RA) in terms of dissociation of N-CoR [8]. This could lead to persistent transcriptional repression, thereby preventing differentiation of promyelocytes. Pharmacologic concentrations of RA, as used in the treatment of APL, result in dissociation of N-CoR, presumably permitting differentiation of the leukemic cells [8].

The binding of the protein product of PML/RAR alpha is thought to repress gene transcription through epigenomic changes including histone deacetylation or methylation [46,47]. One theory holds that PML/RAR alpha creates homodimers that interact with histone methyltransferases, DNA methyltransferases, and histone deacetylases that act as corepressors [47]. Together, they bind and repress expression of differentiation genes thereby blocking differentiation at the promyelocyte stage (figure 1).

A mechanism that 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 [48,49]. In addition, case reports and small trials have reported clinical responses to histone deacetylase inhibitors [50,51].

PML/RAR alpha 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 [52]. On the other hand, PML/RAR alpha in the presence of RA induces apoptosis in association with reduced levels of BCL2 which normally protects against apoptosis [45].

In support of this hypothesis are results obtained with mouse [53] and human [54] multipotent hematopoietic progenitor cells/stem cells (HPC/HSC) transfected in vitro with a retroviral vector containing PML/RARA cDNA. Expression of the PML/RAR alpha fusion protein in human cells dictated the APL phenotype through the following effects [54]:

Rapid induction of human HPC/HSC differentiation to the promyelocytic stage

Maturation arrest at the promyelocytic stage, which was abolished by RA

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

Further mouse studies have demonstrated that expression of PML/RARA supports the immortalization of clonogenic myeloid progenitors also known as leukemia-initiating cells (LICs) [47,55]. The degradation of PML/RAR alpha by RA triggers the loss of these cells. The destruction of LICs, which are immune to the differentiation effects of RA, appears to be a key factor in the eradication of APL.

VARIANT TRANSLOCATIONS — A number of variant translocations have been described in acute promyelocytic leukemia (APL), with t(11;17)(q23;q21.1), t(5;17)(q35;q21.1), and t(11;17)(q13;q21.1) being the most common.

PLZF/RARA and t(11;17) — A variant translocation t(11;17)(q23;q21.1) has been described in approximately 1 percent of patients with APL [18,56]. 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 protein 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 RAR alpha that is fused to PML in cells having t(15;17). The PLZF/RAR alpha fusion protein antagonizes the normal function of RAR alpha/RXR alpha heterodimers, suggesting that it behaves as a dominant negative mutant [57].

Although the number of cases studied is small, APL with t(11;17)(q23;q21.1) is usually refractory to therapy with retinoids, in contrast to the great majority of APL cases with the more common t(15;17) [4,58]. As noted above, PML/RARA in t(15;17) shows reduced sensitivity to retinoic acid (RA), but this can be overcome by pharmacological concentrations of RA. In contrast, pharmacological concentrations of RA do not induce dissociation of N-CoR from PLZF/RAR alpha, leading to persistent transcription repression and prevention of differentiation [8,59].

NPM/RARA and t(5;17) — A rare (less than 0.5 percent) variant translocation in APL has been described, t(5;17)(q35;q21.1), in which the NPM (nucleophosmin) gene was fused to RARA [18,60]. 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 (anaplastic lymphoma kinase) gene. In addition, NPM has been found to fuse to the MLF1 (myeloid leukemia factor 1) gene in t(3;5)(q25.1;q35) in AML. Patients with this translocation are responsive to ATRA therapy [7].

NuMA/RARA and t(11;17) — In the translocation t(11;17)(q13;q21.1), the NuMA (nuclear matrix-mitotic apparatus protein) gene is fused with RARA [7]. Unlike t(11;17)(q23;q21.1), this variant appears responsive to ATRA [61].

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 [62-64].

BCOR/RARA and t(X;17)(q11;q21.1) — A case of APL demonstrating rectangular and round cytoplasmic inclusion bodies was found to have the translocation t(X;17)(q11;q21.1) resulting in a fusion between the BCOR (BCL6 corepressor) gene and RARA [65]. While this case was clinically responsive to ATRA, the patient had several episodes of relapse with standard chemotherapy plus ATRA.

FLT3 MUTATION — FLT3 (FMS-like tyrosine kinase 3) is a transmembrane tyrosine kinase receptor that stimulates cell proliferation upon activation. Mutations in the FLT3 gene producing internal tandem duplications (FLT3-ITD) and constitutive activation of the FLT3 tyrosine kinase are quite common in acute myeloid leukemia (AML), particularly in patients with normal karyotypes, and have been associated with poorer survival in children and in younger and older adults receiving intensive chemotherapy. The impact of FLT3-ITD mutations in patients with acute promyelocytic leukemia (APL) is more controversial.

In one study, FLT3-ITD mutations were identified in 35 of 171 patients (20 percent) with APL treated with all-trans retinoid acid (ATRA) plus anthracycline-based chemotherapy [66]. After a median follow-up of 38 months, FLT3-ITD positivity was associated with inferior overall survival at three years (62 versus 82 percent). While the prognostic impact of FLT3-ITD positivity was maintained on multivariate analysis, FLT3-ITD positivity was strongly associated with other features of severe disease, including high white blood cell counts at the time of presentation.

In another study, FLT3-ITD mutations were identified in 31 percent of 245 patients with APL treated with ATRA plus anthracycline-based chemotherapy with or without arsenic trioxide (ATO) consolidation [67]. FLT3-ITD positivity did not appear to impact remission rate, induction death rate, disease-free survival, or overall survival. ATO consolidation improved outcomes in patients with or without FLT3-ITD mutations.

These studies suggest that FLT3-ITD mutation is not an independent prognostic factor in patients with APL undergoing treatment with both ATO and ATRA-based therapy. FLT3-ITD mutation should not alter treatment decisions in this patient cohort.

Other genetic mutations may also contribute to disease pathogenesis. As an example, whole exome sequencing of 30 patients with newly diagnosed APL demonstrated FLT3 mutations and alterations in other genes (STAG2, U2AF1, SMC1A, USP9X, IKZF1, LYN, MYCBP2, and PTPN11) that have been implicated in other myeloid leukemias [68].

RESISTANCE TO RETINOIC ACID TREATMENT — Mutation analysis has identified several pathways that confer resistance to all-trans retinoid acid (ATRA) therapy in acute promyelocytic leukemia (APL). These genetic changes included acquired mutations in the ligand binding domain of PML-RARA, the acquisition of FLT3-ITD, and additional chromosome abnormalities [69]. A comprehensive mutational analysis of primary and relapsed APL also identified frequent mutations in the PML and RARA genes.

In addition, loss-of-function mutations were found in ARID1B and ARID1A, which encode key components of the SWI/SNF complex [70]. Increased expression of the pseudokinase Tribble 3 (TRIB3) is associated with APL progression and therapeutic resistance; increased TRIB3 expression suppresses the sumoylation, ubiquitylation, and degradation of PML-RAR alpha, which represses PML nuclear body assembly, p53-mediated senescence, and cell differentiation [71].

Management of APL that is resistant to all-trans retinoic acid treatment is discussed separately. (See "Treatment of relapsed or refractory acute promyelocytic leukemia in adults".)

SUMMARY

Acute promyelocytic leukemia (APL) is a biologically and clinically distinct variant of acute myeloid leukemia that is characterized by a translocation involving the RARA (retinoic acid receptor [RAR] alpha) gene on chromosome 17.

RAR alpha is a nuclear steroid/thyroid hormone receptor that is expressed primarily in hematopoietic cells. RAR alpha heterodimerizes with retinoid X receptor (RXR). These RAR alpha/RXR alpha heterodimers interact with the nuclear corepressor N-CoR, a ubiquitous nuclear protein that mediates transcriptional repression and presumably prevents terminal differentiation of promyelocytes. (See 'Retinoic acid and the retinoic acid receptor' above.)

The leukemic cells of more than 90 percent of patients with APL have the balanced translocation t(15;17)(q24.1;q21.1) involving the RARA gene on chromosome 17 and the PML (promyelocytic leukemia) gene on chromosome 15. An additional 5 percent do not have the classic t(15;17), but have the PML/RARA fusion gene, caused by insertions or other complex chromosomal rearrangements. (See 't(15;17) the usual translocation in APL' above.)

The PML gene is expressed ubiquitously and its normal function is not known. Overexpression of PML inhibits growth in cell lines. (See 'The PML gene' above.)

Two novel fusion genes are formed as a result of the t(15;17) (see 'The fusion genes of t(15;17)' above):

A PML/RARA gene on the der(15) chromosome is found in all cases. The resulting rearrangement 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.

An RARA/PML gene on the der(17) can be detected in 80 percent of cases.

The PML/RAR alpha protein functions as an aberrant retinoid receptor expression that blocks retinoic acid induced myeloid differentiation. (See 'Mechanism of action of PML/RARA' above.)

A number of variant translocations have been described in APL that have therapeutic implications (see 'Variant translocations' above):

t(11;17)(q23;q21.1) is seen in approximately 1 percent of patients with APL and it results in the fusion of the RARA gene with the PLZF (promyelocytic leukemia zinc finger) gene, which is expressed in myeloid but not lymphoid lineages. APL with t(11;17)(q23;q11.12) is usually refractory to therapy with retinoids.

t(5;17)(q35;q21.1) is seen in less than 0.5 percent of APL and results in the fusion of the NPM (nucleophosmin) gene to RARA. Patients with this translocation are responsive to ATRA therapy.

t(11;17)(q13;q21.1) results in the fusion of the NuMA (nuclear matrix-mitotic apparatus protein) gene and RARA. This variant appears responsive to ATRA. 

A rare fusion between STAT5B and RARA was found in a patient with an interstitial chromosome 17 deletion and an ATRA-resistant form of APL.

Resistance of APL to ATRA treatment may be associated with mutations in PML, RARA, and other genes. (See 'Resistance to retinoic acid treatment' above.)

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Topic 4523 Version 18.0

References

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