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Hornerin Gene Was Involved in a Case of Acute Myeloid Leukemia Transformed from Myelodysplastic Syndrome with T(1;2)(Q21;Q37)

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Hornerin Gene Was Involved in a Case of Acute Myeloid Leukemia Transformed from Myelodysplastic Syndrome with T(1;2)(Q21;Q37) Letters to the Editor 2184 1 MHV-A59 Department of Infectious Diseases and Immunology, Virology Division, , Utrecht University, Utrecht, The Netherlands and 2Department of Medical Oncology, Division of Gene Therapy, A3.10 VU University Medical Center, Amsterdam, The Netherlands E-mail: [email protected] 3Current address: Molecular Neurogenetics Unit, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. N-CEACAM-Fc References mock 1 Koya RC, Kasahara N, Pullarkat V, Levine AM, Stripecke R. Transduction of acute myeloid leukemia cells with third generation self-inactivating lentiviral vectors expressing CD80 and GM-CSF: effects on proliferation, differentiation, and stimulation of allogeneic and autologous anti-leukemia immune responses. Leukemia 2002; Figure 4 Visualization of the FcgRI-mediated MHV infection of 6 16: 1645–1654. THP-1 cells. An amount of 1 Â 10 TCID50 units MHV-A59 was mixed 5 2 Takada A, Kawaoka Y. Antibody-dependent enhancement of viral with N-CEACAM-Fc or MAb A3.10 and inoculated onto 1 Â 10 THP-1 cells. After 24 h, infected cells were immunofluorescently infection: molecular mechanisms and in vivo implications. Rev Med stained using MHV-specific antibodies. Virol 2003; 13: 387–398. 3 Wallace PK, Howell AL, Fanger MW. Role of Fc gamma receptors in cancer and infectious disease. J Leukoc Biol 1994; 55: 816–826. 4Wu¨rdinger T, Verheije MH, Raaben M, Bosch BJ, de Haan CAM, van Beusechem VW et al. Targeting non-human coronaviruses to Besides coronaviruses, various other viruses have been human cancer cells using a bispecific single-chain antibody. Gene described to use Fc receptors as an alternative entry pathway; Therapy 2005; 12: 1394–1404. examples include HIV, HSV-1, poliovirus, yellow fever virus 5 Wurdinger T, Verheije MH, Broen K, Bosch BJ, de Haan CAM, van and influenza A virus.8 Therefore, the use of antibodies to target Beusechem VW et al. Soluble receptor-mediated targeting of mouse viral vectors to AML cells may also be applicable to other viral hepatitis coronavirus to the human epidermal growth factor receptor. J Virol 2005; 79: 15314–15322. vector systems. Clearly, not every MAb will be able to target a 6 Verheije MH, Wurdinger T, van Beusechem VW, de Haan CAM, particular virus to the FcgRI. However, for several of these Gerritsen WR, Rottier PJM. Redirecting coronavirus to a nonnative viruses specific Fc receptor targeting antibodies have already receptor through a virus-encoded targeting adapter. J Virol 2006; been identified. Compared to other viral vector targeting 80: 1250–1260. strategies, the use of IgG antibodies may offer easy of-the-shelf 7 de Haan CAM, van Genne L, Stoop JN, Volders H, Rottier PJM. targeting potential for the systemic delivery of these viral Coronaviruses as vectors: position dependence of foreign gene expression. J Virol 2003; 77: 11123–11312. vectors. Therefore, further studies on the antibody-mediated 8 Gallagher TM. A role for naturally occurring variation of the murine targeting of viral vectors to Fc receptors expressed on cells of coronavirus spike protein in stabilizing association with the cellular certain types of AML are warranted. receptor. J Virol 1997; 71: 3129–3137. 9 Gilmore W, Fleming JO, Stohlman SA, Weiner LP. Characterization 1,2,3 1,2 1 1 TWu¨rdinger , MH Verheije , LM van der Aa , BJ Bosch , of the structural proteins of the murine coronavirus strain A59 1 2 2 CAM de Haan , VW van Beusechem , WR Gerritsen and using monoclonal antibodies. Proc Soc Exp Biol Med 1987; 185: PJM Rottier1 177–186. Hornerin gene was involved in a case of acute myeloid leukemia transformed from myelodysplastic syndrome with t(1;2)(q21;q37) Leukemia (2006) 20, 2184–2187. doi:10.1038/sj.leu.2404436; Hematologic data were as follows: red blood cells published online 19 October 2006 2.87 Â 1012/l, hemoglobin 83 g/l, white blood cells 14.9 Â 109/ l and a platelet count of 34 Â 109/l. Bone marrow (BM) biopsy: the marrow was hypercellular. The M/E ratio was normal. 1q21–25 is one of the ‘hotspots’ of chromosomal alteration, Myeloblasts and promyelocytes were increased to 28.5%, including duplications and translocations, frequently detected in consistent with myelodysplastic syndrome progression to acute hematological malignancies. As a consequence of these myeloid leukemia. The patient was treated with cyclophos- aberrations, genes may become deregulated or fusion genes phamide, vincristine, cytosine arabinoside and prednisone may be formed and interfere with the normal programs of cell (COAP) combination therapy. Cytogenetic analysis with growth and differentiation. We report here on a patient with R-banding technique on unstimulated BM cells at admission t (1;2)(q21;q37) occurring in acute myeloid leukemia (AML) revealed t(1;2) (q21;q37) chromosome translocation in 10 meta- with antecedent myelodysplastic syndrome (MDS). phases among 11 analyzed (90%) (Figure 1b). Chromosomal The patient was a 71-year-old male (case #30 in SIH-MDS translocation t(1;2) (q21;q37) was also confirmed by chromo- series) who was diagnosed as having progressive MDS. somal painting (CP) using whole CP probes for chromosome 1 Leukemia Letters to the Editor 2185 (digoxigenin-labeled, Oncor, Inc., Gaithersburg, MD, USA) abnormal activation of Hornerin gene detected in the case and chromosome 2(biotin-labeled, Cambio, Cambridge, UK) presented here may play a crucial role in the development and/ (Figure 1c). or progression of MDS in this case. Human Hornerin, which has Chromosome translocation breakpoint on 1q21 was success- been just identified recently, is a member of the ‘fused gene’- fully narrowed into a region which was 15B16 kb upstream to type cornified envelope precursor protein family (profilaggrin, the 50 end of the human Hornerin gene through combination of trichohyalin, repetin and Hornerin).3 Proteins in this family have positional cloning strategy and fluorescence in situ hybridiza- EF-hand domains at the N-terminus followed by multiple tion (FISH) technique. Schema of genetic maps of 1q21 with tandem repeats. The EF-hand Ca2 þ binding domain is highly STS markers as well as YAC, BAC/PAC and plasmid homologic to that of S100 proteins, and these genes are thought contigs localized around the breakpoint on chromosome 1q21 to have evolved through fusion between genes of the S100 Ca2 þ was shown in Figure 1a (Public database referred: http:// binding proteins and genes of cornified envelope precursor www.gdb.org, http://www-genome.wi.mit.edu, http://www.ncbi. proteins. nlm.nih.gov/mapview/, http://www.ensembl.org/index.html, Presently around 20 members of S100 Ca2 þ binding proteins http://bacpac.chori.org and http://www.tigr.org/tdb). YAC have been unveiled, many of which are encoded by genes clones were obtained from CEPH MEGA YAC library and located in a cluster on chromosome 1q21.4 S100 proteins are BAC/PAC clones were purchased from BAC/PAC Resource characterized by common structural motifs including two EF- Center (BPRC) (http://bacpac.chori.org). Dual-color FISH using hands that are separated by a hinge region and flanked by labeled YAC, BAC/PAC or plasmid clones on metaphase of BM amino- and carboxyl-terminal domains. S100 proteins function cells from case #30 were performed as previously described.1,2 as calcium sensor proteins, regulating the function of specific Through FISH/positional cloning procedure illustrated in target proteins upon the activation by calcium binding to Figure 1, we demonstrated that the translocation breakpoint conservative EF-hand motifs. The carboxyl-terminal domain is on 1q21 was within the chromosome region of approximately variable among S100 proteins and is thought to give the specific 20 kb between BAC clones CIT-HSP-2301M16 and R-947A10 biological activity of the individual proteins. (Figure 1f), which was just covered by BAC clone RP11– Several S100 proteins have been implicated in the progres- 107M16 (Figure 1e). sion of cancers in that they have altered levels of expression in Human DNA insert from clone RP11-107M16 (NCBI acces- cancer cells compared to normal cells in addition to sion number AL589986) is 151 kb containing three genes involvement in the immune response, differentiation, cytoske- encoding ‘fused gene’-type cornified envelope precursor pro- leton dynamics and enzyme activity. For example, S100B has teins, trichohyalin, repetin and Hornerin, from centromere to been found to be overexpressed in melanoma, anaplastic telomere on the long arm of chromosome 1. The breakpoint on astrocytoma and glioblastoma.5–7 In the present study, the gene chromosome 1q21 was around Hornerin gene locus. In order to encoding Hornerin, a ‘fused-gene’-type S100 protein, was further characterize the breakpoint region on 1q21, we abnormally activated in the AML case with t(1;2)(q21;q37) constructed a plasmid contig spanning the gap between BAC compared to non-patient BMs. Intriguingly, the expression of clones CIT-HSP-2301M16 and R-947A10 (Figure 1a1). These Hornerin gene was also detected in five among 90 analyzed plasmids contained human DNA fragments of 2B3kb in BM specimens from patients suffering from a variety of average. DNAs from 2 or 3 plasmid clones were pooled malignant hematological diseases. Although cytogenetic ana- together and labeled by nick-translation using Biotin-16-dUTP. lysis did not reveal any chromosome abnormality involving FISH analysis was performed as above. Eventually, we identified chromosome 1q21 in these five samples, some cryptal that plasmid clones 903, 487 and 813, which formed one molecular mechanism might be able to trigger the upregulation combination probe for FISH, covered the translocation break- of Hornerin gene expression in these samples. Whatever point on 1q21. Figure 1g represented the split red signals of this the underlying mechanisms are, the recurrent overexpres- combination probe. Human DNA inserts contained in these sion of Hornerin gene in BMs of leukemia patients may three plasmid clones were 5.4 kb in total, which indicated that potentially contribute to its role in tumor development and/or the translocation breakpoint region was successfully narrowed progression.
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