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ANTICANCER RESEARCH 29: 1031-1038 (2009)

Review RUNX1 Translocations in Malignant Hemopathies

ETIENNE DE BRAEKELEER1,2, CLAUDE FÉREC1,3 and MARC DE BRAEKELEER1,2,4

1National Institute of Health and Medical Research (INSERM) U613, Brest; 2Laboratory of Histology, Embryology and , Faculty of Medicine and Health Sciences, University of Brest, Brest; 3Laboratory of Molecular Genetics and Histocompatibility, and 4Laboratory of Cytogenetics, Cytology and Reproductive Biology, CHU Brest, Brest, France

Abstract. The RUNX family includes three translocations (retaining RHD) that are fused out of frame evolutionarily conserved (RUNX1, RUNX2 and to partner genes are also known. All the translocations that RUNX3) encoding transcription factors involved in cell retain RHD but remove the transcription activation domain lineage differentiation during development and various forms have a leukemogenic effect by acting as dominant negative of cancer. The RUNX1 gene, located in 21q22, inhibitors of wild-type RUNX1 in transcription activation. is crucial for the establishment of definite hematopoiesis and the generation of hematopoietic stem cells in the embryo. It RUNX Gene Family and the RUNX1 Gene contains a “Runt homology domain” (RHD) and a transactivation domain. RUNX1 can act as activator or The RUNX gene family includes three evolutionarily repressor of target depending upon the large conserved genes (RUNX1, RUNX2 and RUNX3) encoding number of transcription factors, coactivators and transcription factors involved in cell lineage differentiation corepressors that interact with it. Three modes of during development and various forms of cancer (1). RUNX1 leukemogenesis due to acquired alterations of the RUNX1 gene, located in chromosome 21q22.3, is crucial for the gene have been recognized: point mutations, amplification establishment of definite hematopoiesis and the generation and translocations. Some translocations have been shown to of hematopoietic stem cells in the embryo, RUNX2, located be recurrent whereas others have been only reported in a few in chromosome 6p21, is essential for osteogenesis and cases or in a sole case. At present, 32 partner RUNX3, located in chromosome 1p36.1, plays a major role have been described but the partner gene has solely been in neurogenesis and thymopoiesis (2, 3). identified in 17 translocations at the molecular level. Most Members of this family share a 128 amino acids region of of the translocations involving RUNX1 lead to the formation high , called “Runt domain”, first of a fusion transcript made of the 5’ region of RUNX1, identified in the runt gene. In addition to this including the RHD, fused to the 3’ region of a partner gene, “Runt homology domain” (RHD), there is a 5 amino acid with the exception of RUNX1-ETV6 in which the 3’ sequence, VWRPY, that is 100% conserved at the C- sequences of RUNX1, including the RHD, are fused to the 5’ terminal end of each of the three gene products (2). The region of ETV6, including its promotor. Three RUNX1 Runt domain is responsible for heterodimerization with the core-binding factor β (CBFβ or PEBP2β) to form a and for DNA binding (4). Presented at the 8th International Conference of Anticancer The Runt-related transcription factor 1 (RUNX1) gene, Research held in Kos, Greece, on October 17-22, 2008. also known as AML1, CBFA2 and PEBP2αB, spans 260 kb and consists of 12 exons with two distinct promoters, each Correspondence to: Professor Marc De Braekeleer, Laboratoire de followed by the initiation codon ATG. These two promoters, Cytogénétique, Faculté de Médecine et des Sciences de la Santé, which are 160 kb apart, generate several alternatively spliced Université de Bretagne Occidentale, 22 avenue Camille Desmoulins, mRNAs differing in their types of 5’ and 3’ UTRs CS 93837, F-29238 Brest cedex 3, France. Tel: +33 0 298016476, Fax: +33 0 298018189, e-mail: [email protected] (untranslated regions) and their coding regions. Although at least 12 different RUNX1 mRNAs are generated, two splice Key Words: RUNX1, fusion gene, translocation, acute , variants are well-characterized. The distal promotor-driven , gene transcription, review. transcript, RUNX1b, encodes a 480 amino acid and

0250-7005/2009 $2.00+.40 1031 ANTICANCER RESEARCH 29: 1031-1038 (2009)

Figure 1. Distribution of the chromosomal arm partners of translocations involving RUNX1. I Recurrent translocations with known partner gene; G Rare translocation with known partner gene; L Rare translocation with unknown partner gene.

the proximal promotor-driven transcript, RUNX1c, a 453 RUNX1 Deregulation amino acid protein. The Runt homology domain is retained in both transcripts (2, 5-7). The full-length coding regions RUNX1 deregulation can be the result of constitutive gene harbor the carboxy-terminal half of the protein which abnormalities. Germ-line point mutations and haploin- regulates transcription (including the transcription activation sufficiency of the RUNX1 gene causes an autosomal dominant and inhibition domains) (8). disorder characterized by familial thrombocytopenia and RUNX1 acts as a key regulator of hematopoiesis through propensity to develop acute myeloblastic leukemia (AML) (13- the regulation of various hematopoietic genes, including 15). The incidence of acute lymphoblastic leukemia is much growth factors (GM-CSF, MPO, IL3), surface receptors higher among patients who are also at an (TCRA, TCRB, M-CSF receptor, FLT3), signaling increased risk of developing acute megakaryoblastic leukemia molecules (CDKN1A, BLK, BCL2), and transcription (AML-M7). It is hypothesized that increased RUNX1 gene activators (STAT3, MYB) (1,9). RUNX1-regulated target dosage is relevant to the high incidence of these hematological genes are essential for definite hematopoiesis of all diseases in children with constitutive 21 (16). lineages (10). Three modes of leukemogenesis due to acquired RUNX1 can act as activator or repressor of target gene alterations of the RUNX1 gene have been recognized. Point expression depending upon the large number of transcription mutations are most frequently found in acute myeloblastic factors, co-activators and co-repressors that interact with it. leukemia (AML) M0 subtype, in myelodysplastic syndrome RUNX1 functions as an organizing protein that facilitates (MDS) and subsequent leukemia, and in therapy-related assembly of transcriptional activation or repression MDS/AML (6, 17). RUNX1 amplification can occur through complexes. By recruitment of non-DNA binding as polysomy of or true amplification. The p300/CBP and HAT (histone acetyltransferase), it amplification could be the result of intrachromosomal contributes to activate transcription of target genes. Upon amplification by tandem repeat or the presence of multiple recruitment of non-DNA binding repressors as mSin3A, copies on double minutes, ring and marker chromosomes Groucho/TLE and HDAC (histone deacetylase), it represses (17-20). Its role in leukemogenesis is still unknown but transcription of target genes (11, 12). RUNX1 amplification induces gene over-expression and

1032 De Braekeleer et al: RUNX1 Translocations in Hemopathies (Review)

Table I. Chromosomal translocations involving the RUNX1 gene.

Translocation Partner gene Gene function References

Recurrent translocations with identified partner gene t(1;21)(p36;q22) PRDM16 Zinc-finger protein, 63% homology with MDS1/EVI1 (42-45) t(3;21)(q26;q22) EVI1 putative transcription factor (34, 59) t(3;21)(q26;q22) MDS1 (27, 34) t(3;21)(q26;q22) EAP Fusion out of frame->truncated RUNX1 (38, 60) t(8;21)(q22;q22) ETO putative transcription factor (22) t(12;21)(p13;q22) ETV6 ETS-related transcription factor (46, 48) t(16;21)(q24;q22) MTG16 (CBFA2T3) Member of ETO family (30, 31, 61) Rare translocations with identified partner gene t(1;21)(p35;q22) YTHDF2 ? (53) t(1;21)(q21.2;q22) ZNF687 Zinc-finger protein, transcription factor (53) t(4;21)(q28;q22) FGA7 ? (54, 62) t(4;21)(q31.3;q22) SH3D19 Src homology 3 (SH3) binding motifs (53) t(7;21)(p22;q21) USP42 Involved in ubiquitin-associated pathways (55) t(8;21)(q23;q22) FOG2 (ZFPM2) Friend of GATA2; Zinc-finger protein (56) t(8;21)(q24;q22) TRPS1 Zinc-finger protein including a GATA-type ZF (63) t(12;21)(q12;q22) CPNE8 Fusion out of frame->truncated RUNX1 (51) t(19;21)(q13;q22) AMP19 Fusion out of frame->truncated RUNX1 (42, 52) t(X;21)(p22;q22) PRDX4 Peroxiredoxin-family gene, antioxydant enzyme (58) Rare translocations with unknown partner gene t(2;21)(p11.2;q22) ? (64) t(2;21)(q21;q22) ? (65) t(4;21)(q21;q22) ? (65) t(4;21)(q31;q22) ? (66) t(5;21)(q13;q22) ? (43, 67) t(6;21)(p22;q22) ? (68) t(8;21)(p13;q22) ? (65) t(9;21)(p21;q22) ? (65) t(10;21)(q21;q22) ? (65) t(12;21)(q24;q22) ? (43) t(14;21)(q13;q22) ? (65) t(14;21)(q22;q22) ? (43) t(14;21)(q24;q22) ? (65) t(15;21)(q22;q22) ? (43) t(17;21)(q11.2;q22) ? (43) t(18;21)(q21;q22) ? (42) t(20;21)(q13;q22) ? (64)

could contribute to transformation of hematopoietic cells (MTG8) gene in the early 1990s (23-25). The RUNX1-ETO (21). Perturbation in RUNX1 function can also be the result fusion gene is identified in some 30% of the patients with of chromosomal translocations. AML-M2 subtype. In the RUNX1-ETO translocation product, the transactivation domain of RUNX1, which RUNX1 Translocations normally binds the transcriptional coactivators p300-CBP, is replaced by almost the entire ETO. As a consequence, the Some translocations involving RUNX1 have been shown to fusion protein recruits a co-repressor complex involving N- be recurrent whereas others have been only reported in a few CoR, mSin3A, SMRT and HDACs instead of the co- cases or in a sole case (Figure 1). At present, 32 partner activators p300-CBP. Therefore, the RUNX1-ETO transcript chromosomes have been described but the partner gene has functions as transcriptional repressor of genes normally solely been identified in 17 translocations at the molecular activated by RUNX1 (26-28). level (Table I). First described by Raimondi et al. in 1989 in a case of Seven partner genes are known to be involved in recurrent AML subtype M1 (29), the t(16;21)(q24;q22) has now been translocations (Table I). The t(8;21)(q22;q22), first described reported in 16 patients, including 12 with AML-M2, eleven by Rowley in 1993 (22), was shown to involve the ETO patients having had for a previous cancer (30,

1033 ANTICANCER RESEARCH 29: 1031-1038 (2009)

61). This translocation was subsequently shown to induce the Ten other partner genes have been identified in rare formation of a new chimeric gene involving the RUNX1 and translocations (42, 51-56, 58, 62-63) (Table I). Several MTG16 (Myeloid Translocation Gene on chromosome 16) transcripts have been characterized. Two RUNX1 genes, the latter belonging to the ETO gene family (31). The translocations (retaining RHD) are fused out of frame to significant homology between MGT16 and ETO suggests partner genes; these are RUNX1-CPNE8 [t(12;21)(q12;q22)] that both RUNX1-MTG16 and RUNX1-ETO fusion genes (51) and RUNX1-AMP19 [t(19;21)(q13;q22)] (52). In the have similar activity (32). The RUNX1-MTG16 protein is an other transcripts that have been characterized, the 5’ region altered transcriptional co-repressor capable of recruiting of RUNX1, including the RHD, is fused to the 3’ region of histone deacetylases, thus repressing the expression of the partner gene (53-58), with the exception of the RUNX1- RUNX1 target genes (33). ZNF687 transcript which induces the lack of RHD and The t(3;21)(q26;q22) translocation is a recurrent transcription activation domain (53). In this case, this would rearrangement observed in patients with de novo or therapy- prevent CBFB binding and transcriptional activation of target related AML, therapy-related MDS and chronic myeloid genes involved in hematopoietic differentiation. leukemia in blastic phase. Three genes have now been Seventeen translocations involving the RUNX1 gene and a shown to fuse with RUNX1. These are EAP, EVI1 and MDS1 yet unknown partner gene have also been described (42- (27, 34-37). 43,64-68) (Table I). The RUNX1-EAP transcript includes the RHD of RUNX1 and the last 96 codons of EAP. The fusion mRNA is Conclusion terminated by an out-of-frame stop codon shortly after the junction between RUNX1 and EAP (27, 34, 38, 39, 60). It is In conclusion, most of the translocations involving RUNX1 likely that the RUNX1-EAP protein acts as a constitutive lead to the formation of a fusion transcript made of the 5’ repressor inhibiting the function of the normal RUNX1. region of RUNX1, including the RHD, fused to the 3’ region The RUNX1-EVI1 transcript includes the RHD of RUNX1 of a partner gene, with the exception of RUNX1-ETV6 in and the two zinc-finger clusters of EVI1. As a consequence, which the 3’ sequences of RUNX1, including the RHD, are RUNX1-EVI1 exerts a dominant negative effect over the fused to the 5’ region of ETV6, including its promotor. wild-type RUNX1 in transcription activation, an anti- Three RUNX1 translocations (retaining RHD) that are fused apoptotic effect (due to the first zinc-finger domain) and a out of frame to partner genes are also known. All the proliferation stimulation effect (due to the second zinc- translocations that retain RHD but remove the transcription finger domain) (40). RUNX1-MDS1/EVI1 is a chimeric in- activation domain have a leukemogenic effect by acting as frame fusion gene of the RUNX1 and MDS1/EVI1 genes dominant negative inhibitors of wild-type RUNX1 in (34, 35, 41, 59) that interferes with RUNX1 functions in a transcription activation. dominant negative manner, but shares some biological effects with EVI1. Acknowledgements The t(1;21)(p36;q22) translocation is a rare, but recurrent, Etienne De Braekeleer is the recipient of a doctoral studentship translocation associated with therapy-related AML/MDS from the “Association de Transfusion Sanguine et de Biogénétique (42-45). It results in a RUNX1-PRDM16 fusion gene which Gaetan Saleun”. This work has been funded in part by the “Ligue retains the RHD of RUNX1 and almost the entire PRDM16 contre le Cancer-Comité du Finistère”. (44, 45). The RUNX1-PRDM16 gene sharing extensive homology with RUNX1-EVI1, it is likely that the RUNX1- References PRDM16 protein acts in a similar way as has been shown for the RUNX1-EVI1 protein (45). 1 Ito Y: Oncogenic potential of the RUNX gene family: ‘overview’. Oncogene 23: 4198-4208, 2004. The t(12;21)(p13;q22) is the most common structural 2 Levanon D and Groner Y: Structure and regulated expression of chromosomal abnormality in pediatric common or B-cell mammalian RUNX genes. Oncogene 23: 4211-4219, 2004. acute lymphoblastic leukemia, accounting for some 25% of 3 de Bruijn MF and Speck NA: Core-binding factors in hemato- the cases (46, 47). At the molecular level, this translocation poiesis and immune function. Oncogene 23: 4238-4248, 2004. fuses the 3’ region of RUNX1 and the 5’ region of ETV6 4 Ito Y: RUNX genes in development and cancer: regulation of (TEL) (48, 49). The ETV6-RUNX1 fusion gene retains the viral gene expression and the discovery of RUNX family genes. RHD and the transcription activation domain of RUNX1 as Adv Cancer Res 99: 33-76, 2008. well as the promoter and the central repression domain of 5 Levanon D, Glusman G, Bangsow T, Ben Asher E, Male DA, Avidan N, Bangsow C, Hattori M, Taylor TD, Taudien S, ETV6. The ETV6-RUNX1 fusion protein retains the ability Blechschmidt K, Shimizu N, Rosenthal A, Sakaki Y, Lancet D to bind the RUNX1 target sequences and has the potential to and Groner Y: Architecture and anatomy of the genomic locus function as a HDAC-dependent repressor, causing encoding the leukemia-associated transcription factor deregulation of the RUNX1 target genes (50). RUNX1/AML1. Gene 262: 23-33, 2001.

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62 Mikhail FM, Serry KA, Hatem N, Mourad ZI, Farawela HM, El 66 Mikhail FM, Serry KA, Hatem N, Mourad ZI, Farawela HM, Kaffash DM, Coignet L and Nucifora G: A new translocation El Kaffash DM, Coignet L and Nucifora G: A new that rearranges the AML1 gene in a patient with T-cell acute translocation that rearranges the AML1 gene in a patient with lymphoblastic leukemia. Cancer Genet Cytogenet 135: 96-100, T-cell acute lymphoblastic leukemia. Cancer Genet Cytogenet 2002. 135: 96-100, 2002. 63 Asou N, Yanagida M, Huang L, Yamamoto M, Shigesada K, 67 Gogineni SK, da Costa M and Verma RS: A new translocation, Mitsuya H, Ito Y and Osato M: Concurrent transcriptional t(5;21)(q13;q22) in acute myelogenous leukemia. Cancer Genet deregulation of AML1/RUNX1 and GATA factors by the AML1- Cytogenet 88: 167-169, 1996. TRPS1 chimeric gene in t(8;21)(q24;q22) acute myeloid 68 Mathew S, Head D, Rubnitz JE and Raimondi SC: Concurrent leukemia. Blood 109: 4023-4027, 2007. translocations of MLL and CBFA2 (AML1) genes with new 64 Richkind K, Hromas R, Lytle C, Crenshaw D, Velasco J, Roherty partner breakpoints in a child with secondary myelodysplastic S, Srinivasiah J and Varella-Garcia M: Identification of two new syndrome after treatment of acute lymphoblastic leukemia. translocations that disrupt the AML1 gene. Cancer Genet Genes, Chromosomes & Cancer 28: 227-232, 2000. Cytogenet 122: 141-143, 2000. 65 Slovak ML, Bedell V, Popplewell L, Arber DA, Schoch C and Slater R: 21q22 balanced chromosome aberrations in therapy- Received October 8, 2008 related hematopoietic disorders: report from an international Revised January 14, 2009 workshop. Genes, Chromosomes & Cancer 33: 379-394, 2002. Accepted February 16, 2009

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