Leukemia (2012) 26, 572–581; doi:10.1038/leu.2011.330; published online 18 November 2011

NKL homeobox genes in leukemia

I Homminga1, R Pieters1 and J P P Meijerink1

1Department of Pediatric Oncology/Hematology, Erasmus MC/Sophia Children's Hospital, Rotterdam, The Netherlands

Correspondence: Dr JPP Meijerink, Dr Molewaterplein 60 Sp2456, GJ Rotterdam 3015, The Netherlands. E-mail:

Received 8 August 2011; Revised 25 September 2011; Accepted 13 October 2011
Advance online publication 18 November 2011



NK-like (NKL) homeobox genes code for transcription factors, which can act as key regulators in fundamental cellular processes. NKL genes have been implicated in divergent types of cancer. In this review, we summarize the involvement of NKL genes in cancer and leukemia in particular. NKL genes can act as tumor-suppressor genes and as oncogenes, depending on tissue type. Aberrant expression of NKL genes is especially common in T-cell acute lymphoblastic leukemia (T-ALL). In T-ALL, 8 NKL genes have been reported to be highly expressed in specific T-ALL subgroups, and in ~30% of cases, high expression is caused by chromosomal rearrangement of 1 of 5 NKL genes. Most of these NKL genes are normally not expressed in T-cell development. We hypothesize that the NKL genes might share a similar downstream effect that promotes leukemogenesis, possibly due to mimicking a NKL gene that has a physiological role in early hematopoietic development, such as HHEX. All eight NKL genes posses a conserved Eh1 repressor motif, which has an important role in regulating downstream targets in hematopoiesis and possibly in leukemogenesis as well. Identification of a potential common leukemogenic NKL downstream pathway will provide a promising subject for future studies.


NKL; homeobox genes; T-ALL



Homeobox genes

In 1894, William Bateson described a distinct kind of transformation within species, which he terms ‘homeosis’, derived from the Greek ‘homoiosis’, which means ‘the same’. He defined it as ‘a change of something into the likeness of something else’.1 Famous examples are the mutant fruit fly Antennapedia, which grows a foot on the head where normally the antenna is located. Another example is a moth (Zygaena), which has an extra wing on the position of a hind leg. Later, the genes held responsible for these variations were called homeotic genes.1 In 1983, two research groups independently identified a 180-bp sequence that was conserved in all homeotic genes, denoted as the homeobox.2, 3 The homeobox is strongly conserved among species and encodes for a DNA-binding domain consisting of three α-helices4 called the homeodomain. By now, >200 human homeodomain proteins are known. Homeodomain proteins are transcription factors that are involved in many key processes such as body patterning, embryonic organogenesis and cell-fate decisions. A mutation in one of these genes can have far-fetching consequences and lead to homeotic transformations such as originally described by Bateson. The classification and nomenclature of homeobox genes have varied substantially between research groups and over time. In 2007, Holland et al.5 proposed a classification for all human homeobox genes based on their hypothetical evolutionary shared ancestry. In all, 11 homeobox gene classes are recognized that comprise a total of 102 homeobox gene families. The largest classes are the ANTP (analogous to the Drosophila antennapedia (antp) gene) and PRD (analogous to the Drosophila paired (prd) gene) classes. The ANTP class can be divided into the HOX-like (HOXL, including the HOXA and HOXB gene clusters) and the NKL (NK-like) subclasses. The involvement of HOXL genes in cancer and leukemia has been extensively reviewed in literature,6, 7, 8, 9, 10, 11 whereas the NKL genes have received less attention. However, recent findings implicate an important role for various NKL genes in human cancer. Therefore, this review will focus on the NKL homeobox genes, their role in cancer and leukemia in particular.

NKL homeobox genes

NKL homeobox genes have important functions in cell-fate specification and embryologic organ development, and their expression is often cell type specific. They are key regulators in fundamental processes as differentiation, proliferation and apoptosis. The NKL subclass comprises 48 genes and 19 assumed pseudogenes (Table 1). All NKL genes have a similar homeodomain. The NKL genes are named after Kim and Nirenberg12 who identified NK1–NK4 genes in 1989 when searching for new genes containing homeobox sequences in Drosophila melanogaster. The human NKL genes can be divided into gene families, which consist of genes that are all derived from a single gene of the latest common ancestor of Drosophila and humans5 (Table 1). In several cases, the gene names are somewhat misleading, frequently suggesting higher similarity than is actually the case. For instance, the human NKX2-3, NKX2-5 and NKX2-6 genes belong to the NK4 family and are most similar to the D. melanogaster NK4 gene. NKX2-1 and NKX 2-4 resemble the Drosophila scarecrow (scro) gene and comprise the Nk2.1 family; NKX2-2 and NKX2-8 are orthologous to the Drosophila ventral nervous system defective (vnd) gene and part of the Nk2.2 family. In addition, not all NKL genes have names that start with NKX, other genes such as TLX1 and TLX3 also belong to the NKL gene subclass (Table 1). The NKL genes are not strongly clustered on the chromosomes in contrast to the HOXA-D genes, although some NKL genes cluster in pairs. This linkage is conserved through species especially for LBX1-TLX1, LBX2-TLX2, NKX2-6-NKX3-1 and HMX2-HMX313 and to a lesser extend for NKX2-1-NKX2-8 and NKX2-2-NKX2-4.14 Initially, clustering is often the result of tandem duplications; however, the conservation of some of these pairs is likely due to shared regulatory regions.13 In humans, several NKL genes are loosely gathered over large areas on chromosome bands 2p13, 4p15–16, 5q35 and 10q23–26 (Table 1).


NKL homeobox genes in cancer

Aberrant expression of NKL homeobox genes may have an important role in oncogenesis. Different abnormalities of NKL genes have been associated with cancer (Table 2). For example, NKX2-1 is amplified in 3–12% of primary lung adenocarcinomas15, 16 and in 33% of lung cancer cell lines.15 However, amplification is significantly less frequent in other types of lung cancer, and deletion of NKX2-1 has been described in squamous lung carcinomas.17 A recent study demonstrated a suppressive effect of NKX2-1 expression on the progression of lung adenocarcinoma.18 This suggests that NKX2-1 can not only function as a tumor-suppressor gene and as an oncogene in lung cancer depending on the subtype but can also have a dual function within a lung cancer subtype.18 Moreover, in the absence of genetic hits, certain NKL homeobox genes have been associated with oncogenesis as crucial downstream targets of established oncogenes, or by effects on proliferation, differentiation or apoptosis (Table 2). For example, NKX2-2 is a critical target of the EWS/FLI fusion protein in Ewing's sarcoma,19 and in clear cell sarcoma, a fusion of EWS/ATF-1 is responsible for NKX6-1 upregulation.20 Hypermethylation of promoter regions of specific NKL genes has also been reported in human cancer, but in most cases, their significance in oncogenesis remains poorly understood (Table 2). Promoter hypermethylation of NKL genes has also been interpreted as a sign of mitotic cell age possibly predisposing for certain types of cancer.21, 22


NKL homeobox genes in leukemia

Leukemia can be divided into myeloid, B- or T-cell leukemia depending on the precursor cell that gave rise to the leukemia. In normal B- and T-cell development, immunoglobulin (heavy and or κ-light chain) and T-cell receptors (TCR-α, TCR-β, TCR-γ or TCR-δ) are rearranged to provide a wide diversity in antigen recognition. This process involves double-stranded DNA breaks, deletion, random addition of nucleic acids and ligation of DNA ends. Dysregulation of this process can result in chromosomal translocations or inversions that may lead to ectopic expression of oncogenes. Such oncogenic translocations are common in hematopoietic malignancies; in fact, >50% of lymphatic leukemias and lymphomas carry chromosomal translocations that involve immunoglobulin or TCR genes.23 To date, many different oncogenes have been identified that are ectopically expressed as a consequence of such translocations. Among these are homeobox genes such as HOXA and HOXB (for review of HOX genes in leukemia, see 7, 8, 9, 10). Thus far, six NKL homeobox genes have been described to be involved in chromosomal translocations or inversions in leukemia and an additional four have been implicated in leukemogenesis by aberrant expression (Table 2).

NKX2-1 and NKX2-2

Our group recently reported on the NKX2-1 and NKX2-2 genes that are amplified (<1%) or involved in TCR or immunoglobulin-driven chromosomal translocations or inversions in ~5% of pediatric T-cell acute lymphoblastic leukemia (T-ALL) patients.24 Repositioning of enhancer regions from TCR or immunoglobulin loci adjacent to NKX2-1 or NKX2-2 results in aberrant activation of these genes. NKX2-1 and NKX2-2 are very-related homeobox genes forming gene families Nk2.1 and Nk2.2 together with NKX2-4 and NKX2-8. Normally, these genes are not expressed in T cells or their precursors,25 and the mechanisms by which they can contribute to leukemia is not yet clear. T-ALL cases harboring these NKX2-1 or NKX2-2 rearrangements shared a gene-expression signature with T-ALL patients harboring a translocation involving TLX1, another NKL gene. It is interesting to note that various TLX1-rearranged T-ALL cases express NKX2-1, although to a lower level compared with NKX2-1-rearranged T-ALL cases. This signature was characterized by a high expression of genes involved in proliferation.24 In most cases, lymphoblasts of these patients are arrested in the early cortical stage of thymocyte development.26, 27, 28, 29

TLX1 (HOX11)

The TLX1 gene is upregulated by translocations in ~7% of pediatric and ~30% of adult T-ALL patients.30, 31, 32, 33 TLX1 aberrations have a been associated with a relative good prognosis.30, 32, 34, 35 Normally, TLX1 is not expressed in adult T cells, thymocytes or hematopoietic stem cells 36, 37, 25 but has a role in spleen and neural development.38, 39, 40 TLX1 immortalizes different hematopoietic cell lineages including T cells,41, 42, 43, 44 and overexpression of TLX1 in transgenic mice results in lymphoid tumors with long latency.42, 45 TLX1 promotes proliferation and blocks differentiation of hematopoietic precursors, thereby contributing to leukemogenesis,41, 42, 43, 46, 47, 48, 49, 50, 51 and TLX1-deregulated T-ALL patients highly express genes that are involved in proliferation.24, 31 TLX1 enhances MYC protein levels by posttranscriptional regulation.52 It also has abrogating effects on cell-cycle check points, for instance, through downregulation of CHEK145 or inhibition of protein serine-threonine phosphatases PP1 and PP2A.51, 53 In addition, TLX1 may increase genomic instability.45

TLX2 (HOX11L1)

TLX2 is normally not expressed in thymocytes,25 but was highly upregulated in a single T-ALL patient in a cohort of 92 patients.54 This patient co-clustered with TLX3-rearranged cases in hierarchical cluster analysis based on microarray gene-expression data,54 suggesting the existence of sporadic T-ALL cases in which the TLX2 gene has an oncogenic role, which is homologous to TLX3-rearranged cases. So far however, no translocation of this gene has been identified in this patient;54 therefore, the role of TLX2 in T-ALL is not yet clear.

TLX3 (HOX11L2)

Approximately 20% of pediatric and 5% of adult T-ALL patients are characterized by TLX3 rearrangements and ectopic expression mostly due to a cryptic translocation t(5;14)(q35;q32),33, 55, 56, 57, 58 placing TLX3 under the influence of the distal enhancer region downstream of BCL11B.31, 33, 55, 59 In sporadic cases, variant TLX3 aberrations have been reported such as translocations to the TRA/D@60 or CDK659 gene, a del5(q35.1)61 or more complex rearrangements involving the 5q35region.59 Alike TLX1 and TLX2, TLX3 is not expressed in normal T-cell development. Leukemogenic modes of actions of TLX3 have not been extensively studied. As TLX1 and TLX3 are closely related genes, a common oncogenic pathway is expected. This is supported by the fact that they can cluster together in gene expression-based hierarchical cluster analysis.24, 31, 62 On the other hand, supervised gene-expressing profiling shows distinct profiles for TLX1- and TLX3-rearranged cases,54 and both groups have a different clinical outcome; TLX1-rearranged patients have a better prognosis than do TLX3-rearranged patients.30, 31, 32, 34, 35, 56, 57, 58, 63 In addition, TLX3 cases are associated with the γδ-lineage and immature T-cell development, whereas TLX1 cases are associated with αβ-lineage commitment.26, 27, 57 TLX1-3 chromosomal aberrations are not reported in other types of cancer.


NKX2-5 translocations to either TRD@ or BCL11B sites are seen in sporadic T-ALL cases.64, 65 A single case of atypical B-cell chronic proliferative disorder has also been described to carry a NKX2-5 translocation.66 NKX2-5 is normally not expressed in thymocytes25, 65 but is involved in spleen and muscle formation. Different pathways that are targeted by NKX2-5 have been proposed to have a role in leukemogenesis. NKX2-5 activates NOTCH3,67 which can enhance survival68, 69 and NKX2-5 causes upregulation of miR-17-92, which may lead to increased proliferation.70 In addition, NKX2-5 binds the promoter of MEF2C and activates MEF2C transcription in T-ALL cell lines.24, 71 Recently, we identified MEF2C as a central oncogene in an immature T-ALL subgroup that shares characteristics with early T-cell precursors (ETP-ALL). In these patients, genetic aberrations were identified that target MEF2C or MEF2C-regulating transcription factors, including NKX2-5.24 During early normal T-cell development, MEF2C is downregulated and ectopic MEF2C expression has been shown to provide a differentiation block.24 MEF2C can also inhibit apoptosis by repressing NR4A1/NUR77, which subsequently prevents transformation of BCL2 into a pro-apoptotic factor.71


ETP-ALL is characterized by early T-cell developmental arrest24, 31, 72 and ectopic expression of LMO2, LYL1 and the NKL homeobox gene HHEX.24, 31 We have previously demonstrated that LMO, LYL1 and HHEX are transcriptional targets of MEF2C.24 HHEX may represent an important transcriptional target gene for this T-ALL subtype, as HHEX itself is sufficient to initiate self-renewal in thymocytes73 and Hex can induce T cell-derived lymphomas when overexpressed in hematopoietic precursor cells in mice.74 HHEX is highly expressed in normal hematopoietic stem cells and downregulation is necessary for normal T-cell development,74, 75 whereas most other hematopoietic lineages maintain HHEX expression.76, 25 So far, no genetic abnormalities of the HHEX gene itself have been found in human T-ALL, although fluorescence in situ hybridization analysis for possible translocations involving the HHEX locus has been extensively performed in patients24 and T-ALL cell lines.67

In acute myeloid leukemia (AML), a NUP98/HHEX fusion has been described due to a t(10;11)(q23;p15).77 NUP98 is often involved in translocations that result in fusion genes and >20 different partner genes have been described. Among these are several other Antp homeobox genes such as HOXA9,78, 79 HOXD1180 and HOXC13.81 For most NUP98–homeodomain fusion proteins, transforming capacities have been demonstrated. The transforming activity seems to depend primarily on the NUP98 N terminus and at least in part on an intact homeodomain.77, 82


NKX3-1 has been found to be overexpressed in TAL1/LMO-rearranged T-ALL.62, 83 Normally, TAL1 is only expressed in the early thymocyte differentiation stages (CD34+, CD1a, CD4 and CD8)84 but it is aberrantly upregulated by interstitial deletions, translocations or unknown mechanisms in >40% T-ALL cases.30, 31, 57, 85, 86 TAL1 can bind to many target genes. One of its target genes is the NKL homeobox gene NKX3-1. TAL1 binds to the NKX3-1 promoter in a complex with LMO, Ldb1 and GATA3 and activates its transcription.83 NKX3-1 in turn seems to be required for T-ALL proliferation and accordingly, genes associated with NKX3-1 expression found by gene-expression analysis were involved in proliferation.83 NKX3-1 was shown to potentially downregulate microRNAs of the miR-17-92 cluster and NKX3-1 and miR-17-92 expressions were inversely correlated.83 However, T-ALL oncogenes NKX2-5 and TLX1 were reported to upregulate these miRNAs in T-ALL70 in line with reported leukemogenic activity of this miRNA cluster in T-ALL models.87 Therefore, the role of miR-17-92 suppression by NKX3-1 in T-ALL is not clear. Normally, NKX3-1 is not expressed in adult tissues except in prostate and testis.88


The NKL gene HLX has been suggested as a potential oncogene in AML and T-ALL. HLX is normally expressed in activated T cells and early hematopoietic progenitors.89, 90 Knock down of HLX in CD34+ bone marrow cells inhibits proliferation, whereas overexpression of HLX impairs differentiation into mature hematopoietic lineages.90 HLX promotes proliferation in the T-ALL cell line Jurkat91 and HLX stably transfected Jurkat cells produce tumors in mice.92 High levels of HLX have been demonstrated in AML patient samples,93 and a single-nucleotide polymorphism in the 3′-untranslated region of HLX is associated with increased risk of therapy-related AML.94 No genetic aberrations of HLX have been found in T-ALL or AML. HLX is not associated with other types of cancer as oncogene or tumor-suppressor gene.


VENTX is highly expressed in a small portion of acute myeloid leukemia patients, especially those with translocation t(8,21) or a normal karyotype,95 but whether it actually has a role in leukemogenesis is not clear. There are inconsistencies in the reports on the expression levels of VENTX in normal hematopoietic lineages. Healthy CD34+ early hematopoietic cells express VENTX at low-to-undetectable levels, whereas mature myeloid cells highly express VENTX.25, 95 Some reports describe VENTX expression in mature B and T cells,96 whereas others have reported a low-to-absent expression in these cell types.95, 25 Enforced expression of VENTX in CD34+ progenitor cells impairs B- and T-cell development, but promotes the development of myeloid cells.95 VENTX knockdown in AML cell lines impairs proliferation, suggesting a possible oncogenic role for VENTX in AML or a role in promoting myeloid phenotype over lymphoid phenotype in preleukemic or leukemic clones.95 In contrast, in chronic lymphoid leukemia, VENTX has been suggested as a potential tumor-suppressor gene96 that functions by inducing cell senescence through the activation of p53 and p16ink4a.97

DLX2, DLX3 and DLX4

In pediatric precursor B-ALL patients carrying a mixed lineage leukemia – ALL1-fused gene from chromosome 4 translocation, decreased levels of DLX2, 3 and 498 have been reported, possibly due to promoter hypermethylation of these genes.99 This points to a tumor-suppressor-like role of these genes in this leukemia type. However, the role of these specific NKL genes in oncogenesis is not clear, as extensive promoter hypermethylation of many genes was recently demonstrated in mixed lineage leukemia – ALL1-fused gene from chromosome 4 translocated infant B-ALL.100 DLX2 and DLX4 are normally highly expressed in healthy B-cell progenitors and downregulated during maturation.


NKL as an oncogene or a tumor-suppressor gene?

As homeobox genes have been initially found to be overexpressed, it has been concluded that homeobox genes act as oncogenes. Nowadays, studies have also reported deletions and downregulation of homeobox genes as important oncogenic events. Hence, NKL genes cannot be considered as ‘classic oncogenes’. Apparently, the same NKL gene can act as an oncogene or as a tumor-suppressor gene depending on the cellular context. In general, it can be stated that homeobox genes that are normally expressed in undifferentiated cells are upregulated in cancer, whereas homeobox genes that are normally expressed in differentiated tissues are downregulated in cancer.101


NKL overexpression as a common theme in T-ALL

It is remarkable that in T-ALL, many different NKL genes are implied in leukemogenesis, especially compared with other types of cancer (Table 2). Approximately 30% of pediatric T-ALL cases harbor a genetic aberration involving a NKL gene (5% NKX2-1, 1% NKX2-2, 6% TLX1, 19% TLX3, 1% NKX2-5). The percentage of cases that overexpress NKL genes is even higher, as TAL1-rearranged cases overexpress NKX3-1 and immature T-ALL cases overexpress HHEX. In addition, high expression of some NKL genes, such as NKX2-1, is observed in some cases in which no genetic aberration was identified. Seven out of eight NKL homeobox genes that are association with T-ALL (NKX2-1, NKX2-2, NKX2-5, NKX3-1, TLX1, TLX2 and TLX3) are part of a separate branch in the phylogenetic tree of the NKL homeobox genes and therefore have a similar homeodomain5 (boxed in Table 1). All these seven genes are not expressed in normal T-cell development. The other gene, HHEX, is part of a separate phylogenetic tree branch and is expressed in early hematopoietic stages and downregulated upon further T-cell maturation. Two different but compatible lineage-dependency models have been proposed for oncogenes, that is, the ‘oncogene-addiction’ model and the ‘lineage-survival model’. As the oncogene-addiction model states that an oncogene will provide a tumor-specific gain of function, the lineage-survival model poses that tumors may become dependent on survival pathways that are already present in precursor cells of the specific cell lineage. The seven NKX and TLX genes mentioned above might be involved in downstream pathways that are normally not involved in T-cell development, but are nonetheless beneficial for survival of thymocytes, in line with the ‘oncogene-addiction model’. On the other hand, these genes might mimic NKL genes that have a role in normal T-cell development, thereby making use of existing pathways, in line with a ‘lineage-survival model’. HHEX49 and MSX267 have both been proposed as candidate genes that might be mimicked by ectopically expressed NKL genes. HHEX is highly expressed in early hematopoietic progenitors and downregulated upon T-cell differentiation. HHEX has also been implicated in leukemogenesis (see above), which makes HHEX a more likely candidate to be mimicked by NKL genes in T-ALL.


NKLs modes of action

NKLs have been implied in different processes essential for oncogenesis especially differentiation, proliferation and apoptosis (see above). The exact mechanisms by which these processes are regulated remain poorly understood. In general, NKL genes function predominantly as transcriptional repressors, although activating properties have also been described.49, 102, 103 More than half (32/48) of the NKL homeodomain proteins contain a conserved Engrailed homology 1 (Eh1) motif (FxIxxIL, whereby x can be any amino acid)104, 105 at their N terminal (defined here as having at least 3 out of 4 conserved amino acids present at the correct position at the N-terminal side, Table 1). The Eh1 domain functions as a strong transcriptional repressor. It can interact with Transducin-like Enhancer-of-split (TLE) co-repressor proteins,106 and these proteins can induce transcriptional repression by recruiting histone deacetylases.107, 108 For HHEX and TLX1, it has been shown that the interaction with TLE proteins is important in regulating downstream targets in hematopoietic lineages and in T-ALL.52, 109 Binding of TLE can result in repression of transcription of NKL targets, but it can also act as a competitive substrate for TLE proteins relieving other factors from TLE-mediated repression and activation of transcription.110 For example, TLX1 expression enhances NOTCH1 signaling in a T-ALL cell line, partly by sequestering TLE from the Hairy/Enhancer of split 1 -TLE-mediated transcriptional repression complex.52, 111 In line with this hypothesis are studies that have identified direct downregulation of TLE proteins by promoter hypermethylation and deletions in acute myeloid leukemia.112, 113 All NKL genes associated with T-ALL have an Eh1-like motif at their N terminal. Therefore, it is tempting to speculate that transcriptional repression through the Eh1 motif and TLE scavenging may be general mechanisms by which NKLs promote leukemogenesis in T-ALL. Besides TLE, GATA proteins also interact with NKL proteins. Together they can activate target genes in muscle and lung tissues.114, 115, 116, 117, 118 What could be important downstream factors of NKL genes, or proteins affected by NKL genes in leukemogenesis? In general, gene-expression analyses have shown enrichment of genes involved in proliferation in TLX1-, TLX3-, NKX2-1/2-2- and NKX3-1-rearranged T-ALL patients.24, 31, 62, 83 Besides a general profile, specific genes or miRNAs have been identified for each of these NKL genes. NOTCH3 has been identified as a recurrent target of NKL proteins TLX1, MSX2 and NKX2-5.67 NOTCH3 overexpression induces T-cell lymphomas in mice68 and is highly expressed in all 30 T-ALL cases examined in a study by Bellavia et al.119 posing a possible important NKL downstream target.


Summary and future implications

NKLs are implicated in divergent types of cancer and can function as oncogenes or tumor-suppressor genes, depending on the tissue type. Oncogenes are downregulated during tissue development in normal tissues, whereas tumor-suppressor genes are normally upregulated during differentiation. Many different NKLs are involved in T-ALL compared with other types of cancer. The overexpression of eight different NKL genes has been associated with T-ALL covering the majority of pediatric T-ALL cases. Most of these NKLs are normally not expressed in T-cell development. This suggests a potential similar downstream effect that promotes leukemogenesis in T-cell progenitors, possibly due to mimicking HHEX. As all eight NKL genes posses a conserved Eh1 repressor motif, this might also have an important role. A common downstream pathway of NKLs might prove difficult to be discovered, especially when most gene-expression analyses are focused on comparisons between subgroups in T-ALL. To elucidate a potential common role of NKL genes in T-ALL, comparisons with normal thymocytes subsets in combination with ChIP (chromatin immunoprecipitation)-on-ChIP or ChIP-seq analysis and functional knockdown and knock-in experiments will be essential.


Conflict of interest

The authors declare no conflict of interest.



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