The ABL1 gene has been found to be fused to four identified partner genes in haematological malignancies. It is rearranged with BCR by the t(9;22)(q34;q11.2) translocation in more than 95% of chronic myeloid leukaemia and in over 25% of adult B-cell acute lymphoblastic leukaemia.1, 2 It is rearranged with TEL (also known as ETV6) in rare cases of chronic myeloid leukaemia and acute leukaemia.3 In T-cell acute lymphoblastic leukaemia, ABL1 can be fused with NUP214 (a gene located in 9q34) on episomes4 or with EML1 by a t(9;14)(q34;q32) translocation.5 Moreover, a recent publication described a t(1;9)(q24;q34) translocation in a B-cell acute lymphoblastic leukaemia case with a putative RCSD1-ABL1 fusion without molecular confirmation.6 Here we report the cytogenetic and molecular analysis of a t(9;10)(q34;q23) translocation, from a case of B-lineage ALL, with recombination of ABL1 to a new partner gene, ZMIZ1 (zinc-finger MIZ-type containing 1).
The patient is an 18-month-old Japanese girl, with no personal or familial medical history other than bronchiolitis and an episode of atopic dermatitis treated with dermocorticosteroids in November 2006. In December 2006, at the age of 14 months, she presented with pallor, asthenia and fever. Physical examination was found normal. Laboratory investigation showed an abnormal white blood cell count (2.2 G l−1 with neutropenia 0 G l−1) and non-regenerative anaemia (Hb 3.5 g per 100 ml). Bone marrow analysis showed heterogeneous density with 3–10% of immature cells. Immunophenotyping analysis of the bone marrow sample did not reveal aberrant surface marker expression. No karyotypic or molecular abnormality was detected at the time. Blood culture was positive for alpha-haemolytic streptococcus. The girl was treated for her septicaemia and transfused. The neutropenia (1.4 G l−1) persisted for 3 months. In April 2007, she presented with fever. Clinical examination was normal. Blood cell count showed bicytopaenia (neutrophils 0 G l−1, Hb 6.6 g per 100 ml). Bone marrow examination showed 90% of CD19+, CD10+, CD34+ CD13−, CD33− lymphoblasts, corresponding to a diagnosis of B-cell acute lymphoblastic leukaemia II, according to the immunological EGIL (European Group for the Immunological Characterization of Acute Leukemias) classification. The patient was then treated abroad, according to the standard risk protocol without kinase inhibitors. She is in first complete remission.
Cytogenetic analysis was performed on bone marrow cells and the karyotype was interpreted as follows: 47,XX,add(9)(q34),del(10)(q?22),+mar/46,XX (Figure 1a). Fluorescent in situ hybridization (FISH) analysis using chromosome painting probes showed a reciprocal translocation between the long arm of chromosomes 9 and 10. FISH using the LSI BCR/ABL1 dual-colour translocation probe showed three red signals, one on the normal chromosome 9, one on the der(9) and another on the der(10), confirming the involvement of ABL1 in the translocation. In order to identify the breakpoint on the der(10) chromosome, FISH was performed with a series of chromosome 10 BAC clones (chosen on the Human Genome Browser Database, University of California at Santa Cruz; http://genome.ucsc.edu). A split signal was observed using RP11-946M14 clone, indicating that it spanned the chromosome 10 breakpoint (Figure 1b). Following FISH experiments, the karyotype could be revised to 47,XX,t(9;10)(q24;q22.3),+mar/46,XX.
Because this clone spans the ZMIZ1 gene lying in an appropriate orientation, we considered it as a candidate fusion partner gene for ABL1. To confirm this hypothesis, we performed PCR with several pairs of specific primers to amplify a putative ZMIZ1-ABL1 fusion transcript. Total RNA isolated from patient bone marrow cells was reverse transcribed using hexamers and Superscript II reverse transcriptase (Invitrogen, Carlsbad, CA, USA). A specific fragment was observed using the following primers: ZMIZ9, 5′-IndexTermAGTATTACAAGCCAGAACAGTTTAATGGA-3′ (NM_020338, nt 1473–1501); ABL2, 5′-IndexTermAGTTCCAACGAGCGGCTTCACTCAGA-3′ (NM_005157, nt 126–151). Sequence analysis of the PCR product revealed that ZMIZ1 exon 14 was fused in-frame with ABL1 exon 2 (Figure 2).
ZMIZ1 is the fifth gene found to be fused to ABL1 in haematological malignancies. It encodes a PIAS (protein inhibitor of JAK-STAT)-like protein, also called hZimp10, known to increase the transcriptional activity of the androgen receptor (AR) and to promote AR sumoylation.7 It has been shown that ZMIZ1 interacts with Smad3 and Smad4 and participates in regulating the TGFβ/Smad pathway via Smad3/4-mediated transcriptional regulation.8 Zmiz1 was recently shown to physically interact with p53 and to increase p53-mediated transcription.9
The ZMIZ1-ABL1 fusion transcript predicts the synthesis of a 197 kDa fusion protein, ZMIZ1-ABL (Figure 2c), containing one of the proline-rich domains of ZMIZ1 and the tyrosine kinase domain of ABL. This proline-rich domain of ZMIZ1 is involved in protein-protein interactions. Similar to other fusion proteins including ABL1, ZMIZ1-ABL1 may encode a constitutively activated tyrosine kinase that promotes cellular transformation. Patients with t(9;10) would therefore be eligible for imatinib treatment.
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We thank S Nusbaum, F Poulain and MC Waill for valuable help. This work was supported by INSERM, L'Association pour la Recherche sur le Cancer (ARC) and INCa Grants PL038 and PL054.
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Soler, G., Radford-Weiss, I., Ben-abdelali, R. et al. Fusion of ZMIZ1 to ABL1 in a B-cell acute lymphoblastic leukaemia with a t(9;10)(q34;q22.3) translocation. Leukemia 22, 1278–1280 (2008). https://doi.org/10.1038/sj.leu.2405033
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