The t(6;9) associated DEK/CAN fusion protein targets a population of long-term repopulating hematopoietic stem cells for leukemogenic transformation

Oancea, Claudia; Rüster, Brigitte; Henschler, Reinhard; Puccetti, Elena; Ruthardt, Martin

doi:10.1038/leu.2010.180

Cited by 42 publications

(67 citation statements)

References 26 publications

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“…This is not surprising considering the fact that LSAs are formed by genetic alterations (chromosomal translocations or gene mutations) that are causally involved in leukemogenesis. [50][51][52][53][54] Several LAAs have also been implicated in the multi-step leukemic transformation of hematopoietic progenitor cells, for example, ETO/MTG8, 55 hTERT 56 and the homeobox protein HOXA9. 57 The LAA WT1 may contribute to leukemogenesis by interfering with normal hematopoietic progenitor cell differentiation, which is considered as one of the first critical steps in the leukemic transformation of these cells.…”

Section: Leukemogenesismentioning

confidence: 99%

Leukemia-associated antigens and their relevance to the immunotherapy of acute myeloid leukemia

2012

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The graft-versus-leukemia effect of allogeneic hematopoietic stem cell transplantation (HSCT) has shown that the immune system is capable of eradicating acute myeloid leukemia (AML). This knowledge, along with the identification of the target antigens against which antileukemia immune responses are directed, has provided a strong impetus for the development of antigen-targeted immunotherapy of AML. The success of any antigen-specific immunotherapeutic strategy depends critically on the choice of target antigen. Ideal molecules for immune targeting in AML are those that are: (1) leukemia-specific; (2) expressed in most leukemic blasts including leukemic stem cells; (3) important for the leukemic phenotype; (4) immunogenic; and (5) clinically effective. In this review, we provide a comprehensive overview on AML-related tumor antigens and assess their applicability for immunotherapy against the five criteria outlined above. In this way, we aim to facilitate the selection of appropriate target antigens, a task that has become increasingly challenging given the large number of antigens identified and the rapid pace at which new targets are being discovered. The information provided in this review is intended to guide the rational design of future antigen-specific immunotherapy trials, which will hopefully lead to new antileukemia therapies with more selectivity and higher efficacy.

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Section: Leukemogenesismentioning

confidence: 99%

Leukemia-associated antigens and their relevance to the immunotherapy of acute myeloid leukemia

2012

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“…Oancea et al reported that Dek is responsible, in part, for the leukemogenic transformation of hematopoietic stem cells. 155 A rare but clinically severe type of acute myeloid leukemia is caused by the t(6;9) chromosomal translocation that creates a fusion gene between DEK and the CAN nuclear pore complex protein. 156 This finding led to the original discovery of DEK, and the fusion protein maintains all but the C-terminal region of the DEK oncogene and is under control of the DEK promoter.…”

Section: Dek Regulates Chromatin Structure and Function In Normal Andmentioning

confidence: 99%

Stacking the DEK: From chromatin topology to cancer stem cells

et al. 2012

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“…15,16 The leukemogenic potential of the fusion protein is restricted to a very small subpopulation of hematopoietic stem cells. 17 The characteristics of t(6;9)/DEK-NUP214 AML have so far not been separately described in pediatric patients and the prognostic impact in pediatric AML is unclear. 1,12,13,18 The aims of this study were to characterize the clinical, genetic and morphological features of t(6;9)-positive childhood myeloid neoplasms in the largest series so far; to evaluate outcome and to identify genes potentially involved in leukemogenesis of t(6;9) using gene expression profiling.…”

Section: Introductionmentioning

confidence: 99%

t(6;9)(p22;q34)/DEK-NUP214-rearranged pediatric myeloid leukemia: an international study of 62 patients

et al. 2014

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IntroductionThe t(6;9)(p22;q34), frequently reported with a breakpoint in 6p23 but now known to involve the DEK gene mapping to 6p22.3, is a rare translocation, estimated to occur in 1-2% of cases of childhood acute myeloid leukemia (AML). 1 The translocation was first identified in 1976, and the first pediatric patient was described in 1982.2,3 The World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia from 2008 listed the t(6;9)(p22;q34) as a distinct entity. 4 However, our current knowledge of t(6;9)(p22;q34) in AML is drawn from relatively small series of patients, predominantly adults, associating t(6;9) with young age at onset and a poor outcome. 1,[5][6][7] Typically, the t(6;9) presents as de novo AML, morphologically associated with FrenchAmerican-British (FAB) type M2, bone marrow basophilia, Auer rods, and dysplasia. 1,5,7,8 The translocation is primarily the sole cytogenetic abnormality (80%); among the 20% of ©2014 Ferrata Storti Foundation. This is an open-access paper. doi:10.3324/haematol.2013 The online version of this article has a Supplementary Appendix. Manuscript received on September 24, 2013. Manuscript accepted on January 13, 2014 Acute myeloid leukemia with t(6;9)(p22;q34) is listed as a distinct entity in the 2008 World Health Organization classification, but little is known about the clinical implications of t(6;9)-positive myeloid leukemia in children. This international multicenter study presents the clinical and genetic characteristics of 62 pediatric patients with t(6;9)/DEK-NUP214-rearranged myeloid leukemia; 54 diagnosed as having acute myeloid leukemia, representing <1% of all childhood acute myeloid leukemia, and eight as having myelodysplastic syndrome. The t(6;9)/DEK-NUP214 was associated with relatively late onset (median age 10.4 years), male predominance (sex ratio 1.7), French-AmericanBritish M2 classification (54%), myelodysplasia (100%), and FLT3-ITD (42%). Outcome was substantially better than previously reported with a 5-year event-free survival of 32%, 5-year overall survival of 53%, and a 5-year cumulative incidence of relapse of 57%. Hematopoietic stem cell transplantation in first complete remission improved the 5-year event-free survival compared with chemotherapy alone (68% versus 18%; P<0.01) but not the overall survival (68% versus 54%; P=0.48). The presence of FLT3-ITD had a non-significant negative effect on 5-year overall survival compared with non-mutated cases (22% versus 62%; P=0.13). Gene expression profiling showed a unique signature characterized by significantly higher expression of EYA3, SESN1, PRDM2/RIZ, and HIST2H4 genes. In conclusion, t(6;9)/DEK-NUP214 represents a unique subtype of acute myeloid leukemia with a high risk of relapse, high frequency of FLT3-ITD, and a specific gene expression signature. t(6;9)(p22;q34)/DEK-NUP214-rearranged pediatric myeloid leukemia: an international study of 62 patients

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The t(6;9) associated DEK/CAN fusion protein targets a population of long-term repopulating hematopoietic stem cells for leukemogenic transformation

Cited by 42 publications

References 26 publications

Leukemia-associated antigens and their relevance to the immunotherapy of acute myeloid leukemia

Leukemia-associated antigens and their relevance to the immunotherapy of acute myeloid leukemia

Stacking the DEK: From chromatin topology to cancer stem cells

t(6;9)(p22;q34)/DEK-NUP214-rearranged pediatric myeloid leukemia: an international study of 62 patients

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