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The recurrent SET-NUP214 fusion as a new HOXA activation mechanism in pediatric T-cell acute lymphoblastic leukemia.

ABSTRACT: T-cell acute lymphoblastic leukemia (T-ALL) is mostly characterized by specific chromosomal abnormalities, some occurring in a mutually exclusive manner that possibly delineate specific T-ALL subgroups. One subgroup, including MLL-rearranged, CALM-AF10 or inv (7)(p15q34) patients, is characterized by elevated expression of HOXA genes. Using a gene expression-based clustering analysis of 67 T-ALL cases with recurrent molecular genetic abnormalities and 25 samples lacking apparent aberrations, we identified 5 new patients with elevated HOXA levels. Using microarray-based comparative genomic hybridization (array-CGH), a cryptic and recurrent deletion, del (9)(q34.11q34.13), was exclusively identified in 3 of these 5 patients. This deletion results in a conserved SET-NUP214 fusion product, which was also identified in the T-ALL cell line LOUCY. SET-NUP214 binds in the promoter regions of specific HOXA genes, where it interacts with CRM1 and DOT1L, which may transcriptionally activate specific members of the HOXA cluster. Targeted inhibition of SET-NUP214 by siRNA abolished expression of HOXA genes, inhibited proliferation, and induced differentiation in LOUCY but not in other T-ALL lines. We conclude that SET-NUP214 may contribute to the pathogenesis of T-ALL by enforcing T-cell differentiation arrest.

SUBMITTER: Van Vlierberghe P

PROVIDER: S-EPMC2343598 | biostudies-literature | 2008 May

REPOSITORIES: biostudies-literature

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The recurrent SET-NUP214 fusion as a new HOXA activation mechanism in pediatric T-cell acute lymphoblastic leukemia.

Van Vlierberghe Pieter P van Grotel Martine M Tchinda Joëlle J Lee Charles C Beverloo H Berna HB van der Spek Peter J PJ Stubbs Andrew A Cools Jan J Nagata Kyosuke K Fornerod Maarten M Buijs-Gladdines Jessica J Horstmann Martin M van Wering Elisabeth R ER Soulier Jean J Pieters Rob R Meijerink Jules P P JP

Blood 20080225 9

T-cell acute lymphoblastic leukemia (T-ALL) is mostly characterized by specific chromosomal abnormalities, some occurring in a mutually exclusive manner that possibly delineate specific T-ALL subgroups. One subgroup, including MLL-rearranged, CALM-AF10 or inv (7)(p15q34) patients, is characterized by elevated expression of HOXA genes. Using a gene expression-based clustering analysis of 67 T-ALL cases with recurrent molecular genetic abnormalities and 25 samples lacking apparent aberrations, we ...[more]

PMID: 18299449

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Project description:T-cell acute lymphoblastic leukemia (T-ALL) is mostly characterized by specific chromosomal abnormalities, some occurring in a mutually exclusive manner possibly delineating specific T-ALL subgroups. One subgroup, including MLL-rearranged, CALM-AF10 or inv(7)(p15q34) cases, is characterized by elevated expression of HOXA genes. Using a gene expression based clustering analysis of 67 T-ALL cases with recurrent molecular genetic abnormalities and 25 samples lacking apparent aberrations, we identified 5 new cases with elevated HOXA levels. Using array-CGH, a cryptic and recurrent deletion, del(9)(q34.11q34.13), was exclusively identified in 3 of these 5 cases. This deletion results in a conserved SET-NUP214 fusion product, that was also identified in the T-ALL cell line LOUCY. SET-NUP214 binds in the promoter regions of specific HOXA genes, where it may interact with CRM1 and DOT1L leading to the transcriptional activation of HOXA genes. Targeted inhibition of SET-NUP214 by siRNA abolished expression of HOXA genes, inhibited proliferation and induced differentiation in LOUCY but not in other T-ALL lines. We conclude that SET-NUP214 may contribute to the pathogenesis of T-ALL by enforcing T-cell differentiation arrest. We combined gene expression profiling and array-CGH analysis to detect a new and recurrent molecular cytogenetic abnormality in T-ALL patients that co-clustered with 5 well-defined HOXA-activated T-ALL samples. We describe the cloning of a recurrent SET-NUP214 fusion product in these samples, and identified a potential mechanism by which SET-NUP214 may activate the HOXA gene cluster as potential leukemogenic event in T-ALL. Experiment Overall Design: For 67 T-ALL patients having one of the major molecular cytogenetic abnormalities (i.e. TAL1 (n=24), LMO2 (n=9), HOXA (n=5), HOX11/TLX1 (n=7), and HOX11L2/TLX3 (n=22)), differentially expressed probesets were calculated from Affymetrix U133plus2.0 data based upon a Wilcoxon analysis and corrected for multiple testing for each probeset. Significant and differentially expressed probesets were obtained for the TAL1, HOX11 and HOX11L2 subgroups. No significant probesets were obtained for the HOXA subgroup or the LMO2 subgroup . As TAL1 and LMO2 both participate in the same transcriptional complex, activation of these genes may both lead to a highly similar expression profile. Combined analysis of TAL1 and LMO2 rearranged cases revealed significant and differentially expressed probesets that, as expected, almost entirely overlapped with the gene signature obtained for the TAL1-subgroup only. Next, we clustered 92 T-ALL cases, that besides the 67 cases as described above further included 25 T-ALL that lacked any of these recurrent abnormalities. Cluster analysis was performed based upon the top 25, 50 or 100 most significant probesets for the TAL1, TAL1/LMO2, HOX11 and HOX11L2 subgroups combined with 15 HOXA probesets identified by Soulier et al (2005)

Project description:SET-CAN/NUP214 fusion is a recurrent event most commonly seen in T-cell acute lymphoblastic leukemia (T-ALL). It is related to resistance to glucocorticoids and chemotherapy; however, the reported prognosis of T-ALL with SET-CAN/NUP214 fusion is diverse, and the optimal treatment option remains undetermined. Here, we present the treatment process of an illuminating case of T-ALL with SET-CAN/NUP214 fusion. The patient showed early resistance to routine VICLP chemotherapy (at 15th day, 79.2% blasts), but the leukemia burden was significantly reduced after 28-day induction chemotherapy (18.85% blasts), even though she still didn't achieve complete remission (CR) after a second course of high-dose methotrexate (3 g/m2) and pegaspargase. Ex vivo drug sensitivity screening using a panel of 165 kinds of cytotoxic drugs, targeted therapy drugs, combination chemotherapy drugs, etc., was conducted on the refractory leukemia cells, which showed extensive resistance to various regimens. Surprisingly, AML-like scheme DAE scheme (daunorubicin + cytarabine + etoposide) and carfilzomib showed the highest ex vivo inhibition rate. The patient received DAE regimen chemotherapy, and finally achieved complete remission and received allogenic hematopoietic stem cell transplantation (allo-HSCT). According to our own findings and a literature survey, we found that T-ALL patients with SET-CAN/NUP214 fusion usually shows early resistance to chemotherapy, but they have a delayed response, and the CR rate is not compromised; thus, a chemotherapy regimen featuring a 28-day long course, such as that used in GRAALL 2003 or 2005, is recommended for induction therapy. For refractory patients, AML-like therapy such as DAE or CLAG in combination with asparaginase may be beneficial. In addition, carfilzomib may be a useful therapeutic drug and is worthy of further study. Allo-HSCT improves prognosis and we recommend HSCT if possible. Additional chromosomal or molecular events may affect the prognosis, and further investigation is needed. We believe that through proper treatment, the prognosis of patients with SET-CAN/NUP214 fusion can be greatly improved, at least not worse than that of other T-ALL patients.

Project description:BACKGROUND: Deregulation of microRNA may contribute to hematopoietic malignancies. MicroRNA-196b (miR-196b) is highly expressed in MLL-rearranged leukemia and has been shown to be activated by MLL and MLL-fusion genes. DESIGN AND METHODS: In order to determine whether high expression of miR-196b is restricted to MLL-rearranged leukemia, we used quantitative stem-loop reverse transcriptase polymerase chain reaction to measure the expression of this microRNA in 72 selected cases of pediatric acute lymphoblastic leukemia i.e. MLL-rearranged and non-MLL-rearranged precursor B-cell and T-cell acute lymphoblastic leukemias. We also determined the expression of HOXA-genes flanking miR-196 by microarray and real-time quantitative polymerase chain reaction. Furthermore, we used CpG island-arrays to explore the DNA methylation status of miR-196b and HOXA. RESULTS: We demonstrated that high expression of miR-196b is not unique to MLL-rearranged acute lymphoblastic leukemia but also occurs in patients with T-cell acute lymphoblastic leukemia patients carrying CALM-AF10, SET-NUP214 and inversion of chromosome 7. Like MLL-rearrangements, these abnormalities have been functionally linked with up-regulation of HOXA. In correspondence, miR-196b expression in these patients correlated strongly with the levels of HOXA family genes (Spearman's correlation coefficient ? 0.7; P?0.005). Since miR-196b is encoded on the HOXA cluster, these data suggest co-activation of miR-196b and HOXA genes in acute lymphoblastic leukemia. Up-regulation of miR-196b coincides with reduced DNA methylation at CpG islands in the promoter regions of miR-196b and the entire HOXA cluster in MLL-rearranged cases compared to in cases of non-MLL precursor B-cell acute lymphoblastic leukemia and normal bone marrow (P<0.05), suggesting an epigenetic origin for miR-196b over-expression. Although patients with MLL-rearranged acute lymphoblastic leukemia are highly resistant to prednisolone and L-asparaginase, this resistance was not attributed to miR-196b expression. CONCLUSIONS: High expression of miR-196b is not exclusively MLL-driven but can also be found in other types of leukemia with aberrant activation of HOXA genes. Since miR-196b has been shown by others to exert oncogenic activity in bone marrow progenitor cells, the findings of the present study imply a potential role for miR-196b in the underlying biology of all HOXA-activated leukemias.

Dataset Information

The recurrent SET-NUP214 fusion as a new HOXA activation mechanism in pediatric T-cell acute lymphoblastic leukemia.

Publications

The recurrent SET-NUP214 fusion as a new HOXA activation mechanism in pediatric T-cell acute lymphoblastic leukemia.

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