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

Abstract

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

DEK oncogene expression during normal hematopoiesis and in Acute Myeloid Leukemia (AML)

“…Data from two studies have revealed that the expression of DEK-NUP214 may increase the overall protein production by targeting translation [6], and may additionally accelerate proliferation through up-regulation of the mTOR pathway [7]. A recent international multicenter study has concluded that DEK-NUP214 represents a unique subtype of AML accompanied by increased risk of relapse, higher FMS-like tyrosine kinase 3 internal tamdem dulpication (FLT3 ITD) mutation frequency and a defined gene signature [8]. However, the precise molecular function of this fusion gene and its disease contribution remain mostly elusive.…”

Leukemia-Associated Nup214 Fusion Proteins Disturb the XPO1-Mediated Nuclear-Cytoplasmic Transport Pathway and Thereby the NF-κB Signaling Pathway

“…Nup214, located at the cytoplasmic filament of the NPC, interacts with NTRs to control macromolecular transport. set-nup214 and dek-nup214 have been identified in acute undifferentiated leukemia and acute myeloid leukemia (AML), respectively (16, 17) and have recently been found in several T-cell acute lymphoid leukemia (T-ALL) and AML patients (18,19). SET-Nup214 has been found to bind to the hoxa locus and activate its expression (20).…”

The DEK oncoprotein and its emerging roles in gene regulation

“…The t(6;9)(p23;q34) has traditionally been associated with poor prognosis, although a recent retrospective study suggests that the outcome for pediatric patients with this translocation may be more similar to that of other childhood AML 66,67 . Patients are generally treated with either chemotherapy or allogeneic hematopoietic stem cell transplantation, with a slightly more favorable prognosis for the latter group 67 .…”

“…However, the specificity of the DEK antibodies used in these studies has been challenged and the concept remains questionable 16,58 The DEK-NUP214 Fusion Gene The (6;9)(p23;q34) chromosomal translocation was originally identified in small subsets of patients with acute myeloid leukemia 63,64 . Recent assessments have estimated that about 1% of all acute myeloid leukemias carry this specific rearrangement [65][66][67] . It is found in both adult and pediatric AML, but the latter form dominates with a mean age of diagnosis of 23 years 66 .…”

“…Patients are generally treated with either chemotherapy or allogeneic hematopoietic stem cell transplantation, with a slightly more favorable prognosis for the latter group 67 . In 1992, the (6;9)(p23;q34) translocation was characterized as a fusion between specific introns in the gene encoding the chromatin architectural protein DEK and the gene encoding the nucleoporin NUP214 (originally termed CAN) 17 .…”