Two multi-partner genes, PRDM16 and ETV6, are rearranged in an aggressive acute myeloid leukemia associated with a translocation t(1;12)(p36.3;p12)
Geneviève AmeyeMarie‐Christiane VekemansPascale SaussoyAugustin FerrantHélène A. PoirelJeanne‐Marie LiboutonKatrina RackC. VachaudezKhadija BahloulaC. Meutter
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Acute lymphoblastic leukaemia (ALL) is one of the most common malignancies of childhood. Many factors affecting the prognosis of ALL have been reported, and risk stratification according to these markers has shown consistently good correlation with survival of the patients (Carroll et al, 2003). Among these prognostic factors, the t(12;21)(p13;q22) ETV6-RUNX1 rearrangement is well-known. Some patients with ETV6-RUNX1 rearrangements (ETV6-RUNX1+) show fusion signals of ETV6-RUNX1 without the native ETV6 signal (Kempski & Sturt, 2000; Park et al, 2001; Romana et al, 1995; Woo et al, 2005), which result implies deletions of the untranslocated ETV6 gene region or the entire chromosome 12. However, the clinical significance of native ETV6 deletion has not been established. We conducted this study to determine the clinical implication of native ETV6 deletion in childhood ETV6-RUNX1+ ALL. A total of 216 newly diagnosed childhood ALL patients, treated at Seoul National University Children’s Hospital, were included from March 1998 to October 2009. Fluorescent in situ hybridization (FISH) for the common rearrangements –ETV6-RUNX1, BCR-ABL1, and MLL rearrangements – and CDKN2A deletions were performed using VYSIS probe (Vysis, Downers Grove, IL, USA). In ETV6-RUNX1+ patients showing loss of native ETV6 signals, the number of chromosomes 12 was assessed using chromosome enumeration probe (CEP) 12 for the discrimination of monosomy 12 and true deletion. Retrospective analysis of the patient records was conducted. The relapse-free survival (RFS), event-free survival (EFS) and overall survival (OS) of the patients were analysed. An event was defined as the occurrence of relapse or death associated with treatment/disease progression. Twenty-nine children with ETV6-RUNX1 rearrangements with complete clinical and laboratory information were analysed further. Among them, 20 (69·0%) had native ETV6 deletions without evidence of monosomy 12. Previously known prognostic factors showed no statistically significant differences between the patients with or without native ETV6 deletions. Interestingly, 50% of ETV6-RUNX1+ patients with native ETV6 deletions showed blasts>25% in bone marrow aspirates on day 7 of induction therapy, while none of ETV6-RUNX1+ patients without native ETV6 deletions showed blasts >25%. However, relapse and death during the course of the study occurred only in the patients without native ETV6 deletions. A Kaplan–Meier plot of RFS, EFS and OS revealed favourable prognosis in the ETV6-RUNX1+ patients with native ETV6 deletions, compared to those without deletions (Fig. 1, P < 0·05). The OS of ETV6-RUNX1+ patients with native ETV6 deletions was comparable to those of patients with hyperdiploidy, other cytogenetic abnormalities or no cytogenetic abnormalities (P = 0·468). Additionally, ETV6-RUNX1+ patients without native ETV6 deletions showed an OS that was not significantly different from those of patients with CDKN2A deletions or complex abnormalities (P = 0·985). From these observations, our patients were categorized into three groups: those with good prognosis (hyperdiploidy, ETV6-RUNX1+ with native ETV6 deletions, other abnormalities, or no cytogenetic abnormalities), intermediate prognosis (ETV6-RUNX1+ without native ETV6 deletions, CDKN2A deletions, or complex abnormalities), and poor prognosis (BCR/ABL1 rearrangements or MLL abnormalities). Each group showed characteristically distinct prognosis (Fig. 2, P < 0·001). Kaplan–Meier analysis of overall (A), relapse-free (B), and event-free (C) survival in ETV6-RUNX1+ patients with and without native ETV6 deletions. Kaplan–Meier analysis of overall survival according to the prognostic factors. Good: patients with hyperdiploidy, ETV6/RUNX1 rearrangements with native ETV6 deletions, other cytogenetic abnormalities, or no cytogenetic abnormalities; Intermediate: patients with ETV6/RUNX1 rearrangements without native ETV6 deletions, CDKN2A deletions, or complex abnormalities; Poor: patients with BCR/ABL1 rearrangement or MLL abnormalities. See text for more detail. None of the analysed variables could explain differences in the survivals of the patients at statistically significant levels on the Cox’s regression analysis. Nonetheless, the hazard ratios (HR > 200) of native ETV6 deletions strongly suggested that it might be responsible for the apparent differences in prognosis displayed in the Kaplan–Meier analysis. This paradoxical phenomenon might arise from the fact that the prognosis of children with ETV6-RUNX1 rearrangements is so good that few patients show relapse or death in the follow-up period. Such rare events can lower the statistical significance in the Cox’s regression analysis. And comparison between the two groups revealed no significant difference in the distribution of other prognostic variables. Previous studies on the prognostic effects of native ETV6 deletions have reported inconsistent results (Attarbaschi et al, 2004; Chung et al, 2010). However, these studies did not count the number of chromosomes 12, so they could not estimate the presence of monosomy 12. This might have great impact on interpretation of the data, as hypodiploidy is one of the common abnormalities found in childhood ALL. In the present study, native ETV6 deletions occurred in 69·0% of patients with ETV6-RUNX1 rearrangements, but the incidence of ETV6 deletions varied widely from 11·1% to 75·0% in previous studies involving relatively small numbers of patients (4–38 patients) (Kempski & Sturt, 2000; Park et al, 2001; Romana et al, 1995; Woo et al, 2005). Moreover, none of these studies investigated the presence of monosomy 12. The number of enrolled patients in our study was relatively larger than those of the previous studies. Additionally, we could estimate fairly precisely the prevalence of native ETV6 deletions using CEP 12 analysis. Early response of bone marrow to induction therapy is a well-known prognostic factor in ALL, especially in standard and high-risk groups (Schultz et al, 2007). However, in our study, native ETV6 deletions accompanied by ETV6-RUNX1 rearrangements tended to harbour favourable prognostic effects despite the high blast count at day 7 of chemotherapy. This result suggests the presence of different biological properties between the groups and may include factors such as proliferating activity or sensitivity to therapeutic agents. The putative role of the ETV6 protein appears to be as a cell cycle suppressor that induces G1 arrest in the cell cycle and suppresses Ras-mediated proliferation (Rompaey et al, 2000). One previous study using an acute myeloid leukaemia (AML) cell line reported that loss of CDKN1A (p21) in AML cells leads to increased proliferative activity, but decreased stem cell-like properties (Viale et al, 2009). Native ETV6 deletions might have similar effects on ALL stem cells as suggested by the finding that more patients showed slow early responses at induction day 7 but better long-term prognosis in the deletion group. Further studies are needed for the verification of this hypothesis. In conclusion, we found that native ETV6 deletions in ETV6-RUNX1+ childhood ALL is associated with better prognosis among ETV6-RUNX1+ childhood ALL. We propose that native ETV6 deletions in ETV6-RUNX1+ childhood ALL may be a novel prognostic factor and a very low risk factor for risk stratification of childhood ALL patients. This work was supported in part by (1) a grant (10172KFDA993) from Korea Food & Drug Administration in 2010 (2) the Korea Science and Engineering Foundation (KOSEF) funded by the Ministry of Education, Science, and Technology (20100020584).
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The ETV6 gene encodes an ETS family transcription factor that is involved in a myriad of chromosomal rearrangements found in hematological malignancies and other neoplasms. A recurrent ETV6 translocation, previously described in patients with acute myeloid leukemia (AML) (Genes Chromosomes Cancer 51:328-337,2012, Leuk Res 35:e212-214, 2011), whose partner has not been identified is t(7;12)(p15;p13). We herein report that the t(7;12)(p15;p13) fuses ETV6 to ANLN, a gene not previously implicated in the pathogenesis of hematological malignancies, and we demonstrate that this translocation leads to high expression of the fusion transcript in the myeloid and lymphoid lineages.
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Abstract T‐cell acute lymphoblastic leukemia (T‐ALL) is the result of multiple oncogenic insults of thymocytes. Recently, new ABL1 fusion genes have been identified that provide proliferation and survival advantage to lymphoblasts. These are the NUP214‐ABL1 fusion gene, on amplified episomes, the unique case of EML1‐ABL1 fusion due to a cryptic t(9;14)(q34;q32) and the seldom reported BCR‐ABL1 and ETV6‐ABL1 chimeric genes. The most frequent and strictly associated with T‐ALL is the NUP214‐ABL1 fusion identified in 6% of cases, in both children and adults. Patients present with classical T‐ALL features. Cytogenetically, the fusion is cryptic but seen by FISH on amplified episomes or more rarely as a small hsr. The ABL1 fusion is a late event associated with other genetic alterations like NOTCH1 activating mutation, deletion of CDKN2A locus, and ectopic expression of TLX1 or TLX3 . The mechanism of activation of the NUP214‐ABL1 protein is unique and requires localization at the nucleopore complex and interaction with other nuclear pore proteins for crossphosphorylation and constitutive kinase activity. The ABL1 fusion proteins are sensitive to tyrosine kinase inhibitors, which can be included in future treatment strategy. © 2010 Wiley‐Liss, Inc.
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The chromosomal translocation t(7;11)(p15;p15) and the resulting nucleoporin 98-homeobox A9 (NUP98-HOXA9) gene fusion is rare but recurrent genetic abnormity in acute myeloid leukemia (AML). The present study describes a case of AML plus maturation (‑M2) with multilineage dyspoiesis in a 30‑year‑old male in whom a 46,XY,t(7;11)(p15;p15) karyotype was detected through chromosome analysis. Subsequent molecular and sequencing analysis demonstrated a NUP98‑HOXA9 fusion gene with a type I fusion between NUP98 exon 12 and HOXA9 exon 1b, and mutations in neuroblastoma V‑Ras oncogene homolog and Wilms tumor 1. The patient achieved hematological complete remission (CR) following two courses of induction chemotherapy. However, the NUP98‑HOXA9 fusion gene remained detectable during the hematological CR period and following intensive consolidation chemotherapy. The disease relapsed 11 months after diagnosis, and the patient became refractory, with complications from an infection causing eventual mortality. The present case and literature review suggest that patients with AML and t(7;11) may have unique biological and clinical characteristics, and a poor prognosis.
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BCL6
Lymphopoiesis
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Objectives: E26 transformation-specific variant 6 gene (ETV6) is one of the most consistently rearranged genes in acute leukaemia. It encodes a principal hematopoietic transcription factor.Methods: We performed a systematic review focusing on the mechanisms responsible for etv6 acquisition, and its effect on the development of AML. We also review the Characteristics of ETV6 mutations and its fusion genes. Finally, for using ETV6 as a molecular target, we discuss future therapeutic approaches available to mitigate the associated disease.Results: ETV6 rearrangements often accompany other molecular mutations. Thirty-three distinct partner bands of ETV6 that contain various fusion genes were detected which plays a vital role in obtaining information about leukaemia genesis. RXDX-101 and PKC412 were reported to be inhibitors of ETV6-NTRK3.Discussion: Future researches are needed to explain how ETV6 mutations act within the microenvironment of leukemic cells and how it affects the progression of leukaemia.
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