ETV6 (TEL1) in Blood Cell Development and Malignancy

    

    

    Figure 1:  ETV6 chromosomal location, gene and protein structure. Schematic representation of the ETV6 gene locus on human chromosome 12 (upper panel), the ETV6 gene transcript with numbered boxes corresponding to exons (middle panel), and the ETV6 protein with domains indicated and relevant amino acids numbered (lower panel).
    
    

The PNT domain is responsible for homo or heterodimerization with a range of proteins, including the closely-related ETV7 protein, the ETS family member FLI1 and the ubiquitin-conjugating enzyme UBC9 [6,7,11,12]. This domain is required for the repression of target genes [13], and also mediates the nuclear export of ETV6, thereby regulating its activity [14]. The positively charged ETS domain is responsible for binding to DNA [15,16]. The less conserved central domain contributes to the repression activity of ETV6 [17-21].

In several studies ETV6 has been identified as a strong transcriptional repressor [17,18]. This has been mapped to the PNT and central domains. PNT domain-mediated repression has been shown to be dependent on interaction with the SPM domain of L3MBTL1 (human homolog of the Drosophila Lethal3 Malignant brain tumor protein), a member of polycomb group of chromatinassociated proteins, which stabilizes the repressive effect of ETV6 on transcription through a HDAC (histone deacetylase) independent mechanism [22]. In contrast, repression by the central domain is mediated through binding of various co-repressors, including SMRT, mSin3A, N-CoR and Tip60, which subsequently recruit HDACs to mediate transcriptional repression [17-21].

While ETV6 would appear to regulate the transcription of genes with ETS consensus site in their promoters, only a handful of genes actually targeted by ETV6 are known. These include the GPIIb and GPIbα genes in myeloid K562 cells induced with TPA [23], the TCL1 (T-cell lymphoma 1) oncogene in pre-B cell acute lymphoblastic leukemia cells [24], the BCL-XL gene in NIH 3T3 cells [13] and β-globin in transgenic mice expressing human ETV6 under the control of Gata1 promoter [25] as well as acting on the Stromelysin (MMP3) promoter in Ras-transformed NIH3T3 cells [26].

Role of ETV6 in vivo

ETV6 has been shown to play an important role in normal embryonic development and hematopoietic regulation. Targeted knockout of the Etv6 gene in mice led to embryonic lethality at day 10.5-11.5 of development due to mesenchymal and neural cell apoptosis accompanied by defective angiogenesis in the yolk sac [27]. Primary erythropoiesis at this time was unaffected. However, further analysis of chimerical mice consisting of Etv6^-/- cells and normal (Etv6+/+) cells revealed that although Etv6^-/- cells contributed to yolk sac and fetal liver hematopoisis, they were totally absent from the bone marrow. These findings revealed that Etv6 was essential for the establishment of definitive hematopoisis in mice [28]. Knockdown of etv6 in Xenopus also revealed a requirement for this gene in the formation of the first definitive hematopoietic stem cells in the dorsal aorta [29]. Conditional knockouts in adult mice indicated that Etv6 was essential for survival of adult HSCs within hematopoietic niches [30]. However, ablation of Etv6 after lineage commitment did not affect adult hematopoietic except for specific maturation defects in the megakaryocytic lineage [30].

In contrast, transgenic mice expressing human ETV6 under the control of Gata1 promoter revealed that ETV6 was also involved in both proliferation and differentiation in the erythroid lineage, depending on the stage of erythroid development. During the early stages of erythropoiesis, ETV6 was found to accelerate proliferation, while in the latter stages it increased differentiation including stimulation of hemoglobin synthesis. The latter was achieved through indirect promotion of ALAS-E transcription and direct stimulation of β-globin synthesis [25]. This may explain the observation that enhanced expression of ETV6 in mouse erythroleukemia cells induced their differentiation toward erythrocytes [31]. Recent studies in zebrafish have confirmed a broad role for ETV6 in embryonic hematopoiesis, impacting on progenitor cells, as well as erythroid, myeloid and lymphoid populations [32].

Chromosomal translocations involving ETV6 in hematological malignancy

The human ETV6 gene is notable for its frequent involvement in chromosomal translocations associated with hematological malignancies. Approximately 50 translocations involving the ETV6 gene have been described, involving around 30 partner genes [33]. These translocations can be classified according to the type of fusion partners namely: tyrosine kinases, transcription factors and other proteins (Figure 2).

Figure 2: Graphical representation of the various proteins found fused to ETV6 in malignancy are shown by class: tyrosine kinases (blue), transcription factors (green) and other proteins (orange).

    

    

    Figure 2:  Graphical representation of the various proteins found fused to ETV6 in
malignancy are shown by class: tyrosine kinases (blue), transcription factors
(green) and other proteins (orange).
    
    

Close

Tyrosine kinases

The ETV6/tyrosine kinase fusions have been detected in a plethora of hematological malignancies. In all cases, including fusions with ABL1, ABL2, JAK2, SYK, FRK, LYN, FGFR3, PDGFRA, PDGFRB, NTRK3 and FLT3, the PNT domain of ETV6 is fused to the tyrosine kinase domain of the fusion partner. In this way the PNT domain mediates dimerization of the tyrosine kinase, resulting in its constitutive activation with subsequent autophosphorylation and phosphorylation of downstream signal transducing proteins, such as STATs (Table 1). The use of animal models has revealed new insights into the function of these fusion oncoproteins, for example ETV6-JAK2 [34,35].

Table 1: Tyrosine kinase fusions with ETV6.

  

    
Fusion gene 
    
Disease 
    
Translocation 
    
Breakpoint in ETV6 
    
PNT 
    
ETS 
    
Functional mechanisms 
    
References 
  
  

    
ETV6-ABL1 
    
AML, B-cell ALL, T-cell ALL, MPN, CML (Ph negative) in    CP and BP
    
t(9;12)
    
int 4 or 5
    
+
    
-
    
� Constitutive activation of PTK domain of ABL1
    
[45-49]
  
  

    
ETV6-ABL2 
    
AML-M4, M3, T-cell ALL
    
t(1;12)
    
int 5
    
+
    
-
    
� Constitutive activation of PTK domain of ABL2
    
[50-52]
  
  

    
ETV6-JAK2 
    
Pre-B cell ALL, aCML, T-cell ALL
    
t(9;12)
    
int 4 or 5
    
+
    
-
    
� Constitutive activation of PTK domain of JAK2
    
[53,54]
  
  

    
ETV6-FGFR3 
    
Peripheral T-cell lymphoma
    
t(4;12)
    
int 5
    
+
    
-
    
� Constitutive activation of PTK domain of FGFR3
    
[55]
      
 
  
  

    
ETV6-SYK 
    
MDS
    
t(9;12)
    
int 5
    
+
    
-
    
� Constitutive activation of PTK domain of SYK
    
[56]
  
  

    
ETV6-FRK 
    
AML-M4
    
t(6;12)
    
int 4
    
+
    
-
    
� Constitutive activation of PTK domain of FRK
    
[57]
  
  

    
ETV6-LYN 
    
Primary myelofibrosis
    
Ins(12;8)
    
int 5
    
+
    
-
    
� Constitutive activation of PTK domain of LYN
    
[58]
  
  

    
ETV6-PDGFRA 
    
MPN
    
t(4;12)
    
int 6
    
+
    
-
    
� Constitutive activation of PTK domain of PDGFRA
    
[59]
  
  

    
ETV6-PDGFRB 
    
CMML, AML-M0 on CIM, AML-M2, aCML in Bc
    
t(5;12)
    
int 4 or 7
    
+
    
-
    
� Constitutive activation of PTK domain of PDGFRB
    
[59-62]
  
  

    
ETV6-NTRK3 
    
AML-M2, M0, CEL
    
t(12;15)
    
int 4 or 5
    
+
    
-
    
� Constitutive activation of PTK domain of NTRK3
    
[63-65]
  
  

    
ETV6-FLT3 
    
MPN with hypereosinophilia, T-lymphoblastic lymphoma
    
t(12;13)
    
int 4 or 5
    
+
    
-
    
� Constitutive activation of PTK domain of FLT3
    
[66,67]
  

Table 1:  Tyrosine kinase fusions with ETV6.

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Transcription factors

ETV6/transcription factor fusions have been implicated in variety of leukemias. In these cases, the fusion modifies the transcription activity of ETV6 and/or the fusion partner by converting a transcriptional repressor into an activator or vice versa, which can be achieved in three different ways. Fusions with involvement of the PNT domain of ETV6, such as fusions with RUNX1 and ARNT, result in a dominant-negative effect of the fusion protein over the normal function of the fusion partner. However, in fusions that involve both PNT and ETS domains of ETV6, such as fusions with MN1, PAX5 and HLXB9, the chimeric protein appears to act as an aberrant transcription factor and results in modification of both ETV6 and partner protein transcription activity. Finally, in fusions that involve the promoter - rather than a functional domain - of ETV6, such as with EVI1 and CDX2, ectopic expression of the fusion partner genes in hematopoietic cells has been suggested to mediate leukemogenesis (Table 2).

Table 2: Transcription factor fusion partners of ETV6.

  

    
Fusion gene 
    
Disease 
    
Translocation 
    
Breakpoint in ETV6 
    
PNT 
    
ETS 
    
Functional mechanisms 
    
References 
  
  

    
ETV6-RUNX1 
    
B-cell ALL
    
t(12;21)
    
int 4 or 5
    
+
    
-
    
� Dominant negative effect of the fusion protein over    wild type ETV6 allele
      
� Repression of RUNX1 target genes
    
[37,68,69]
  
  

    
MN1-ETV6 
    
AML-M0, M2, M4, CML, RAEB, AML on MDS
    
t(12;22)
    
int 2 or 3
    
+
    
+
    
� Activation of ETV6 target genes
      
� Repression of retinoic acid mediated transcription
      
� Dominant negative effect of the fusion protein over    wild type MN1 allele
    
[70-76]
  
  

    
ETV6-ARNT 
    
AML-M2, T-cell ALL
    
t(1;12)
    
int 4
    
+
    
-
    
� Dominant negative effect of the fusion protein over    wild type ETV6 allele
      
� Modification of ARNT into a transcriptional    repressor.
    
[77,78]
  
  

    
ETV6-EVI1 
    
aCML, Bc-CML, RAEB, AML-M0
    
t(3;12)
    
int 2
    
-
    
-
    
� Ectopic expression of EVI1
    
[53,79,80
  
  

    
ETV6-CDX2 
    
AML-M1
    
t(12;13)
    
int 2
    
-
    
-
    
� Ectopic expression of CDX2
    
[50,81]
  
  

    
PAX5-ETV6 
    
B-cell ALL
    
t(9;12)
    
int 2
    
+
    
+
    
� Modification of ETV6 and/or PAX5 transcription    activity
    
[82,83]
  
  

    
HLXB9-ETV6 
    
AML-M0, M1, M2,�    M3, M7
    
t(7;12)
    
int 2
    
+
    
+
    
� Modification of ETV6 and/or HLXB9 transcription    activity?
    
[84-87]
  

Table 2:  Transcription factor fusion partners of ETV6.

Close

Other proteins

Other ETV6 translocations not involving tyrosine kinases or transcription factors have been reported in variety of leukemias. In most of these cases, just the first two exons of ETV6 are involved in the translocation. It is believed that in these cases, involving fusions to CHIC2, MDS2, TTL, STL, ACS2 and PER1, the over expression of a neighboring gene is the critical pathogenic mechanism of the translocation (Table 3).

Table 3: Other protein fusion partners of ETV6.

  

    
Fusion gene 
    
Disease 
    
Translocation 
    
Breakpoint in ETV6 
    
PNT 
    
ETS 
    
Functional mechanisms 
    
References 
  
  

    
CHIC2-ETV6 
    
AML-M0,M1,M2, M/NK cell leukemia, RAEB
    
t(4;12)
    
int 1 or 2
    
-
    
-
    
� Overexpression of adjacent gene (GSX2)
    
[88-92]
  
  

    
ETV6-MDS2 
    
RAEB
    
t(1;12)
    
int 2
    
-
    
-
    
� Overexpression of adjacent gene (PRL11)
    
[89]
  
  

    
ETV6-TTL or 
      
TTL-ETV6 
      
 
    
Pre B-cell ALL
    
t(12;13)
    
int 1
      
 
    
-
      
+
    
-
      
+
    
� Loss of function of ETV6 or/and TTL
      
� Overexpression of adjacent genes (p27 and FOXO1A)?
    
[93]
  
  

    
ETV6-STL or 
      
STL-ETV6-S or STL-ETV6-L, M 
    
Pre-B ALL
    
t(6;12)
    
int 2
    
-
      
+
      
-
    
-
      
+
      
-
    
� Deregulation of adjacent gene (OSTL*)
      
� Loss of ETV6 function
    
[94]
  
  

    
ETV6-PER1 
    
AML on CMML
    
t(12;17)
    
int 1
    
-
    
-
    
� Overexpression of adjacent gene (HES7 or STK12)
    
[95]
  
  

    
ETV6-ACS2 
    
RAEB, MDS, AML, AEL, PV, CML
    
t(5;12)
    
int 1 or 2
    
-
    
-
    
� Overexpression of adjacent gene (IL-3)
    
[89,96-99]
  
  

    
ETV6-PTPRR 
    
AML-M2
    
inv(12)
    
int 4
    
+
    
-
    
� Dominant negative effect of the fusion protein over    wild type ETV6 allele
    
[100]
  
  

    
ETV6-NCOA2 
    
AML-M2, ALL
    
t(8;12)
    
int 4 or 5
    
+
    
-
    
� Constitutive activation of ETV6 target genes
      
� Modification of transcriptional activity of    CBP-dependent activators
    
[101]
  
  

    
ETV6-BAZ2A 
    
Pre B-cell ALL
    
t(12;12)
    
int 2
    
-
    
-
    
� Haploinsufficiency of ETV6 and/or BAZ2A?
      
� Deregulation of BAZ2A or a gene in vicinity of BAZ2A?
    
[43]
  
  

    
ETV6-GOT1 
    
RA, RAEB
    
t(10;12)
    
int 2 or 3
    
-
    
-
    
� Dominant negative effect of fusion protein over both    GOT and ETV6
    
[102,103]
  
  

    
ETV6-FCHO2 
    
AML-M1
    
t(5;12;22)
    
int 2
    
-
    
-
    
� Haploinsufficiency of ETV6 and/or FCHO2
    
[42]
  
  

    
ETV6-IGH 
    
Pre B-cell ALL
    
t(12;14)
    
?
    
?
    
?
    
?
    
[104]
  

Table 3:  Other protein fusion partners of ETV6.

Close

Tumor suppressor function of ETV6

Besides being involved in a vast number of translocations associated with hematological malignancies, there are other studies supporting the notion that ETV6 functions as a tumor suppressor gene. The short arm of chromosome 12 is a hot spot for chromosomal abnormalities in various hematological malignancies, these include interstitial deletions that lead to the loss of genetic material from 12p which has been mapped to a small locus containing the ETV6 and KIP1 genes [36]. In many cases of childhood ALL carrying t(12;21) the wildtype ETV6 allele is deleted [9,37,38]. Interestingly, in cells harboring these translocations, consistent loss of ETV6 expression was observed even in the absence of detectable ETV6 deletion, suggesting that secondary structural abnormalities and epigenetic modifications may lead to the silencing of ETV6 allele [38]. Frequent point mutations of ETV6 have been reported in T-ALL and AML leading to truncated forms of ETV6 which exerted a dominant-negative effect to abolish wild type ETV6 function [39-41]. Furthermore, in several cases of leukemia including ETV6 translocations, neither functional fusion protein was identified nor was ectopic expression of a neighboring proto-oncogene reported. In these cases, haploinsufficiency of ETV6 has been raised as a contributing factor in the etiology of leukemia [42,43].

Additional evidence of a potential tumor suppressor role for ETV6 comes from its functional studies. A transient increase in endogenous ETV6 expression was also reported during the first 3 days of differentiation of Mouse Erythroleukemia (MEL) cells [31]. Over-expression of ETV6 in these cells enhanced erythroid differentiation while introduction of a dominant-negative mutant of ETV6 completely blocked this process with cells continuing to proliferate. Enforced expression of ETV6 inhibited cell growth in Rastransformed cells [26] and retarded proliferation of both primary wild type and immortalized cells possibly through inducing G1 arrest [44] or decreasing survival via direct repression of the Bcl-X_L promoter [13]. It has also been demonstrated that ETV6 over expression slowed the Ras-induced tumor formation in nude mice [44].

Conclusion

ETV6 remains best known for its role as a hot spot for translocation, yielding a large number of chromosomal fusions important in the etiology of hematological malignancy. However, more recent studies have indicated that the encoded protein is both a tumor suppressor and an important regulator of hematopoiesis, which provides new insights into how its disruption contributes to malignancy. Key questions remaining for future research are, firstly, which genes are targeted by ETV6 in both its tumor suppressor and oncogenic roles and, secondly, whether pharmacologic agents can be developed to either enhance the former or hinder the latter.

Acknowledgment

The work was supported by funding from Deakin University via an International Postgraduate Research Scholarship (to PR) and an Alfred Deakin Postdoctoral Research Fellowship (to CL). The authors have no conflicts of interest to declare.

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Citation: Rasighaemi P, Liongue C and Ward AC. ETV6 (TEL1) in Blood Cell Development and Malignancy. J Blood Disord. 2014;1(3): 1012. ISSN 2379-8009

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