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Atlas of Genetics and Cytogenetics in Oncology and Haematology INIST-CNRS OPEN ACCESS JOURNAL Leukaemia Section Short Communication t(1;21)(p22;q22) RUNX1/CLCA2 Amélie Giguère, Josée Hébert Quebec Leukemia Cell Bank and Division of Hematology-Oncology, Maisonneuve-Rosemont Hospital, Montreal, Quebec, H1T 2M4, Canada (AG, JH) Published in Atlas Database: June 2012 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0121p22q22ID1608.html DOI: 10.4267/2042/48236 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology Treatment Clinics and pathology The pediatric patient was treated with cytarabine, mitoxantrone and amsacrine. At complete remission, he underwent an allogeneic stem cell transplantation with a conditioning regimen including etoposide and total body irradiation. At relapse, the boy underwent a second bone marrow transplantation. The adult patient was treated with a standard induction chemotherapy regimen (infusional cytarabine combined with daunorubicine) and two cycles of consolidation therapy with high doses cytarabine, followed by a reduced intensity allogeneic stem cell transplantation. The t(1;21) positive t-AML was not treated with chemotherapy. The patient received palliative care. Disease Therapy-related acute myeloid leukemia (t-AML) Epidemiology Two AML cases positive for the t(1;21)(p22;q22) were reported, a 9 year-old boy (Nadal et al., 2008) and a 64 year-old man (Giguère and Hébert, 2010). Clinics The 9 year-old boy presented in September 2004 with an initial diagnosis of acute myeloid leukemia with maturation (AML-M2) with a normal karyotype. In December 2004, he underwent an allogeneic bone marrow transplantation and then relapsed in June 2006. At relapse, the karyotype was 46,XY,t(1;21)(p22;q22)[15]/46,XX[5]. The adult patient developed a de novo AML-M2 with an abnormal karyotype 45,XY,-7[17]/46,XY[3] in December 2005. He received a standard induction and consolidation chemotherapy followed by an allogeneic hematopoietic stem cell transplantation. In August 2007, he developed a t(1;21)(p22;q22) positive t-AML. Complete blood count showed a white blood cell count of 16.4 x 109/L, hemoglobin of 86 g/L and platelet count of 34 x109/L. The bone marrow aspirate showed 52% of blast cells. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(11) Evolution The boy was alive in April 2012 (Nadal, personal communication). The adult patient died one month and 18 days following t-AML development. Prognosis Undetermined. Genetics Note FLT3-ITD (FLT3 internal tandem duplication) mutation was detected in the pediatric patient's leukemic cells and was absent in the adult patient's cells. 852 t(1;21)(p22;q22) RUNX1/CLCA2 Giguère A, Hébert J Partial GTG-banded karyotype showing derivative chromosomes 1 and 21 involved in the t(1;21)(p22;q22). Metaphasic FISH using the LSI RUNX1-RUNX1T1 dual color translocation probe (Abbott Molecular). Three green signals (21q22, RUNX1 gene) are shown (arrows), indicating the presence of a RUNX1 rearrangement. Two normal red signals (8q22, RUNX1T1 gene) were observed. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(11) 853 t(1;21)(p22;q22) RUNX1/CLCA2 Giguère A, Hébert J Additional anomalies Cytogenetics The t(1;21) was the sole anomaly in t-AML cells. Cytogenetics morphological Can be easily identified using G-banded chromosomes. Genes involved and proteins Cytogenetics molecular RUNX1 FISH using the RUNX1-RUNX1T1 probe showed splitted signals located on derivative chromosomes 1 and 21. RUNX1 rearrangement was confirmed using the RP11299D9 BAC probe (BACPAC Resources Center) (Giguère and Hébert, 2010). Location 21q22 DNA/RNA The RUNX1 gene contains 8 coding exons spanning 260 kilobases (kb) of genomic DNA. The RUNX1 gene and protein are represented. Exons 3 to 5 code for the DNA binding Runt homology domain (RHD) whereas exons 7 and 8 encode the transcriptional regulatory domain which includes activation (TA) and inhibitory domains (ID). The CLCA2 gene and protein are represented. The calcium-activated chloride channel (CLCA), the von Willebrand factor type A domain (VWA) and a domain of unknown function (DUF1973) are encoded by amino acids 8 to 265, 312 to 470 and 494 to 674 respectively, according to the PFAM website (http://pfam.sanger.ac.uk). Main fusion transcript resulting in a fusion of RUNX1 exons 1-6 to CLCA2 exons 2-14. Transcription orientation: telomere to centromere. Protein RUNX1 is a conserved member of the RUNX family and is a master regulator of hematopoiesis through activation or repression of lineage-specific genes. The protein was proposed to function as a regulator of chloride current and to act as a potential tumor suppressor in breast cancer cells (Gruber and Pauli, 1999; Elble and Pauli, 2001). Result of the chromosomal anomaly CLCA2 Location 1p22.3 DNA/RNA The CLCA2 gene contains 14 exons which spans 32 kb of genomic DNA. Transcription orientation: telomere to centromere. Protein CLCA2 is a member of the calcium-activated chloride channel family. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(11) Hybrid gene Description 5' RUNX1-CLCA2 3'. Transcript At least six out-of-frame fusion transcripts were identified (Giguère and Hébert, 2010). 854 t(1;21)(p22;q22) RUNX1/CLCA2 Giguère A, Hébert J Nadal N, Stephan JL, Cornillon J, Guyotat D, Flandrin P, Campos L. RUNX1 rearrangements in acute myeloblastic leukemia relapsing after hematopoietic stem cell transplantation. Cancer Genet Cytogenet. 2008 Jan 15;180(2):168-9 Fusion protein Note In this case, RUNX1-CLCA2 fusion transcripts lead to truncated RUNX1 proteins (Giguère and Hébert, 2010). References Giguère A, Hébert J. CLCA2, a novel RUNX1 partner gene in a therapy-related leukemia with t(1;21)(p22;q22). Cancer Genet Cytogenet. 2010 Oct 15;202(2):94-100 Gruber AD, Pauli BU. Tumorigenicity of human breast cancer is associated with loss of the Ca2+-activated chloride channel CLCA2. Cancer Res. 1999 Nov 1;59(21):5488-91 This article should be referenced as such: Giguère A, Hébert J. t(1;21)(p22;q22) RUNX1/CLCA2. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(11):852-855. Elble RC, Pauli BU. Tumor suppression by a proapoptotic calcium-activated chloride channel in mammary epithelium. J Biol Chem. 2001 Nov 2;276(44):40510-7 Atlas Genet Cytogenet Oncol Haematol. 2012; 16(11) 855