Blast phase of chronic myeloid leukemia with concurrent BCR::ABL1 and SET::NUP214: A report of two cases.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm defined by the presence of t(9;22)(q34;q11.2)/BCR::ABL1. Additional chromosomal abnormalities play an important role in the progression to CML. However, the additional fusion gene was rarely reported such as CBFB::MYH11. In this report, we described two cases of the co-occurrence of BCR::ABL1 and SET::NUP214 in CML-BP for the first time, which is associated with poor outcomes during tyrosine kinase inhibitor (TKI) treatment. Meanwhile, we retrospectively analyzed SET::NUP214 fusion transcript of the two cases at initial diagnosis of the CML chronic phase by quantitative RT-PCR, and detected at a ratio of 1.63% and 1.50%, respectively. SET::NUP214 may promote disease progression during the transformation of CML. This study highlights the importance of extended molecular testing at the initial diagnosis of CML-CP at TKI resistance and/or disease transformation.

SET-NUP214 and MLL cooperatively regulate the promoter activity of the HoxA10 gene.

SET-Nup214 is a recurrent fusion gene that is mainly observed in T-cell acute lymphoblastic leukemia (T-ALL). Dysregulation of homeobox (Hox) genes is frequently observed in patients with leukemia. Consistent with this, HoxA genes are upregulated in the SET-Nup214 + T-ALL cell line and patients. Although SET-Nup214 has been reported to be recruited to the promoter regions of HoxA genes, the detailed mechanisms of how SET-Nup214 specifically binds to HoxA gene promoters and regulates HoxA gene expression are not known. In this study, we demonstrated that SET-Nup214 interacts with MLL via the SET acidic region of SET-Nup214. SET-Nup214 and MLL cooperatively enhance the promoter activity of the HoxA10 gene. Neither the SET region alone nor the Nup214 region alone sufficiently enhanced the HoxA10 gene promoter. Our results indicated that the SET portion of the SET-Nup214-fusion protein is important for interactions with MLL and transcription enhancement of the HoxA10 gene. Thus, our study will contribute to the understanding of how SET-Nup214 and MLL disturb the expression of HoxA10 gene in leukemia.

Chidamide maintenance therapy after allo-HSCT in SET-NUP214 fusion positive T-ALL patients: A report of two cases.

T-cell acute lymphoblastic leukemia (T-ALL) is a highly invasive hematological malignancy originated from T-lineage progenitor cells. The clonal proliferation and aggregation of primordial cells in bone marrow inhibit normal hematopoietic function, resulting in a series of hematocytopenia and infiltration symptoms. SET-NUP214 fusion is a recurrent event that is common in adult male T-ALL patients. It originates from chromosome del(9)(q34.11; q34.13) or t(9; 9)(q34; q34). Hematopoietic stem cell transplantation (HSCT) can significantly improve the survival rate of these patients. Due to the poor prognosis of patients and high relapse rate after remission, more effective strategies need to be proposed to improve prognosis and prevent relapse. Chidamide is a novel oral benzamide histone deacetylase inhibitor (HDACi) that can exert anti-tumor effects through multiple mechanisms. Here we report chidamide maintenance therapy after allo-HSCT in patients with SET-NUP214 fusion positive T-ALL. Both patients improved effectively during follow-up, confirming the efficacy of chidamide in improving the condition of these patients and may provide valuable clinical information for the treatment of this rare and understudied disease.

[Clinical Analysis of SET-NUP214 Fusion Gene Positive Patients with Acute Leukemia].

OBJECTIVE: To analyze the characteristics and prognosis of acute leukemia(AL) with SET-NUP214 fusion gene. METHODS: The clinical data of 17 patients over 14 years old newly diagnosed with SET-NUP214 positive AL admitted in Institute of Hematology and Blood Diseases Hospital from August 2017 to May 2021 were analyzed retrospectively. RESULTS: Among the 17 SET-NUP214 positive patients, 13 cases were diagnosed as T-ALL (ETP 3 cases, Pro-T-ALL 6 cases, Pre-T-ALL 3 cases, Medullary-T-ALL 1 case), AML 3 cases (2 cases M5, 1 case M0) and ALAL 1 case. Thirteen patients presented extramedullary infiltration at initial diagnosis. All 17 patients received treatment, and a total of 16 cases achieved complete remission (CR), including 12 cases in patients with T-ALL. The total median OS and RFS time were 23 (3-50) months and 21 (0-48) months, respectively. Eleven patients received allogeneic hematopoietic stem cell transplantation(allo-HSCT), with median OS time of 37.5 (5-50) months and median RFS time of 29.5 (5-48) months. The median OS time of 6 patients in chemotherapy-only group was 10.5 (3-41) months, and median RFS time of 6.5 (3-39) months. The OS and RFS of patients with transplantation group were better than those of chemotherapy-only group (P=0.038). Among the 4 patients who relapsed or refractory after allo-HSCT, the SET-NUP214 fusion gene did not turn negative before transplantation. While, in the group of 7 patients who have not relapsed after allo-HSCT till now, the SET-NUP214 fusion gene expression of 5 patients turned negative before transplantation and other 2 of them were still positive. CONCLUSION: The fusion site of SET-NUP214 fusion gene is relatively fixed in AL patients, often accompanied by extramedullary infiltration. The chemotherapy effect of this disease is poor, and allo-HSCT may improve its prognosis.

[Analysis of the clinical characteristics of 24 cases of hematological malignancies with SET-NUP214 fusion gene].

Objective: To investigate the expression of SET-NUP214 fusion gene in hematological malignancies and to analyze its related clinical biological characteristics. Methods: The clinical data of 24 patients with SET-NUP214 fusion gene-positive hematological malignancies were retrospectively analyzed, and the Kaplan-Meier method was used for survival analysis. Results: Among the 24 patients with SET-NUP214 fusion gene, 15 cases of acute lymphoblastic leukemia (ALL) (13 cases of T-ALL and 2 cases of B-ALL) , 7 cases of acute myeloid leukemia (AML) , and 2 cases of T/myeloid mixed acute leukemia have been identified. The immunophenotype of 13 cases of T-ALL was mainly characterized by CD3(+)CD2(-), 73.3% of ALL was characterized by myeloid marker expression, and 85.7% of AML was characterized by CD7 expression. Complete remission (CR) was achieved in 22 patients (91.7%) after induction chemotherapy. All 24 patients received allogeneic hematopoietic stem cell transplantation (HSCT) . With a median follow-up of 24 months, the 3-year relapse free survival (RFS) of AML and ALL was 85.7% and 33.3%, respectively (P=0.128) . Comparing 13 cases of SET-NUP214-positive and 62 cases of SET-NUP214-negative T-ALL, the CR rates of induction chemotherapy were 92.3% and 93.5% (P=0.445) , and the 4-week CR rates of induction chemotherapy were 69.2% and 72.6%, respectively (P=0.187) ; the differences were not statistically significant. After HSCT, the 3-year RFS of SET-NUP214(+)T-ALL and SET-NUP214(-)T-ALL was 38.5% and 66.4%, respectively (P=0.028) , and the difference was statistically significant. Conclusion: The SET-NUP214 fusion gene is mainly detected in T cell-derived hematological malignancies, and the prognosis of SET-NUP214 positive T-ALL is relatively poor.

SET-NUP214 Fusion Gene Involved Early T-Cell Precursor Acute Lymphoblastic Leukemia in Adult with B Marker Expression.

Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is rare and associated with poor clinical outcome especially in adults. ETP tumor cells that express cross-lineage antigens or lack pan T markers usually pose big challenges to diagnosis, and their prognostic implications are therefore more uncertain. This study reports the unique case of a 44-year-old woman with breast mass as the initial presentation of acute leukemia possessing both T- and B-cell features (cytoplasmic CD3+CD7+CD19+CD79a+). Despite the presence of gene rearrangements of IGH and IGK probably in a small amount of B cells, the patient was diagnosed with T-ALL mainly according to WHO criteria, and further ETP-ALL rather than mixed phenotype ALL based on additional positive expression of stem/myeloid lineage antigens (CD34+CD13+CD33+HLA-DR+). Moreover, in spite of normal karyotype, SET-NUP214 gene fusion is identified, which has not been described in ETP-ALL with bi-phenotype. After intensive chemotherapy, the patient achieved short-term morphologic complete remission but relapsed within one month. This report may expand immunophenotype and clinical behavior of ETP-ALL in adults. Comprehensive evaluations are emphasized in making a differential diagnosis and distinguishing subtypes of acute leukemia.

Disclosing the Interactome of Leukemogenic NUP98-HOXA9 and SET-NUP214 Fusion Proteins Using a Proteomic Approach.

The interaction of oncogenes with cellular proteins is a major determinant of cellular transformation. The NUP98-HOXA9 and SET-NUP214 chimeras result from recurrent chromosomal translocations in acute leukemia. Functionally, the two fusion proteins inhibit nuclear export and interact with epigenetic regulators. The full interactome of NUP98-HOXA9 and SET-NUP214 is currently unknown. We used proximity-dependent biotin identification (BioID) to study the landscape of the NUP98-HOXA9 and SET-NUP214 environments. Our results suggest that both fusion proteins interact with major regulators of RNA processing, with translation-associated proteins, and that both chimeras perturb the transcriptional program of the tumor suppressor p53. Other cellular processes appear to be distinctively affected by the particular fusion protein. NUP98-HOXA9 likely perturbs Wnt, MAPK, and estrogen receptor (ER) signaling pathways, as well as the cytoskeleton, the latter likely due to its interaction with the nuclear export receptor CRM1. Conversely, mitochondrial proteins and metabolic regulators are significantly overrepresented in the SET-NUP214 proximal interactome. Our study provides new clues on the mechanistic actions of nucleoporin fusion proteins and might be of particular relevance in the search for new druggable targets for the treatment of nucleoporin-related leukemia.

Chromatin-bound CRM1 recruits SET-Nup214 and NPM1c onto HOX clusters causing aberrant HOX expression in leukemia cells.

We previously demonstrated that CRM1, a major nuclear export factor, accumulates at Hox cluster regions to recruit nucleoporin-fusion protein Nup98HoxA9, resulting in robust activation of Hox genes (Oka et al., 2016). However, whether this phenomenon is general to other leukemogenic proteins remains unknown. Here, we show that two other leukemogenic proteins, nucleoporin-fusion SET-Nup214 and the NPM1 mutant, NPM1c, which contains a nuclear export signal (NES) at its C-terminus and is one of the most frequent mutations in acute myeloid leukemia, are recruited to the HOX cluster region via chromatin-bound CRM1, leading to HOX gene activation in human leukemia cells. Furthermore, we demonstrate that this mechanism is highly sensitive to a CRM1 inhibitor in leukemia cell line. Together, these findings indicate that CRM1 acts as a key molecule that connects leukemogenic proteins to aberrant HOX gene regulation either via nucleoporin-CRM1 interaction (for SET-Nup214) or NES-CRM1 interaction (for NPM1c).

Clinical Analysis of SET-NUP214 Fusion Gene Positive Patients with Acute Leukemia / 中国实验血液学杂志

OBJECTIVE@#To analyze the characteristics and prognosis of acute leukemia(AL) with SET-NUP214 fusion gene.@*METHODS@#The clinical data of 17 patients over 14 years old newly diagnosed with SET-NUP214 positive AL admitted in Institute of Hematology and Blood Diseases Hospital from August 2017 to May 2021 were analyzed retrospectively.@*RESULTS@#Among the 17 SET-NUP214 positive patients, 13 cases were diagnosed as T-ALL (ETP 3 cases, Pro-T-ALL 6 cases, Pre-T-ALL 3 cases, Medullary-T-ALL 1 case), AML 3 cases (2 cases M5, 1 case M0) and ALAL 1 case. Thirteen patients presented extramedullary infiltration at initial diagnosis. All 17 patients received treatment, and a total of 16 cases achieved complete remission (CR), including 12 cases in patients with T-ALL. The total median OS and RFS time were 23 (3-50) months and 21 (0-48) months, respectively. Eleven patients received allogeneic hematopoietic stem cell transplantation(allo-HSCT), with median OS time of 37.5 (5-50) months and median RFS time of 29.5 (5-48) months. The median OS time of 6 patients in chemotherapy-only group was 10.5 (3-41) months, and median RFS time of 6.5 (3-39) months. The OS and RFS of patients with transplantation group were better than those of chemotherapy-only group (P=0.038). Among the 4 patients who relapsed or refractory after allo-HSCT, the SET-NUP214 fusion gene did not turn negative before transplantation. While, in the group of 7 patients who have not relapsed after allo-HSCT till now, the SET-NUP214 fusion gene expression of 5 patients turned negative before transplantation and other 2 of them were still positive.@*CONCLUSION@#The fusion site of SET-NUP214 fusion gene is relatively fixed in AL patients, often accompanied by extramedullary infiltration. The chemotherapy effect of this disease is poor, and allo-HSCT may improve its prognosis.

B-cell acute lymphoblastic leukemia associated with SET-NUP214 rearrangement: A case report and review of the literature.

The SET nuclear proto-oncogene (SET)-nucleoporin (NUP)214 fusion gene, which results from cryptic t(9;9)(q34;q34) or del(9)(q34.11q34.13), is a rare genetic event in hematological malignancies. The majority of patients carrying SET-NUP214 experience T-cell acute lymphoblastic leukemia (T-ALL), but rarely experience acute undifferentiated leukemia or acute myeloid leukemia. The current study presents the case of a 19-year-old male patient with B-cell ALL (B-ALL) carrying the SET-NUP214 fusion gene, in addition to an fms-related tyrosine kinase 3-internal tandem duplication mutation and a complex karyotype abnormality. The patient exhibited chemotherapy resistance. To the best of our knowledge, the present study is the first report of a case of B-ALL carrying the SET-NUP214 fusion gene, and provides a review of the literature.

Adult acute T-lymphocytic leukemia patients with SET-NUP214 fusion gene: report of four cases and review of literature / 白血病·淋巴瘤

Objective To analyze the clinical and biological characteristics of adult acute T-lymphocytic leukemia (T-ALL) patients carrying SET-NUP214 fusion gene,and the prognostic value of SET-NUP214 molecular marker monitoring.Methods The clinical and laboratory data of 4 adult T-ALL patients with SET-NUP214 fusion gene in the Third People's Hospital of Chengdu from January 2009 to December 2014 were analyzed retrospectively,and T cell receptor (TCR) gene rearrangement was detected to judge the differentiation and developmental stages of tumor cells in these patients.Minimal residual disease (MRD) was detected in 2 patients with follow-up specimens through detection of SET-NUP214 gene by using polymerase chain reaction.Results Four patients expressed T cell immune markers CD5,CD7,and cytoplasmic CD3 (cyCD3),and also expressed some myeloid-specific antigens.All 4 patients had the same SET-NUP214 fusion site.In the tumor cells of 4 patients,5 TCRB gene rearrangements were detected,all of which were incomplete rearrangement of DB-JB;4 patients were detected with TCRG and TCRD gene rearrangements,and all were completely rearranged.The result of MRD monitoring through SET-NUP214 fusion gene was consistent with clinical treatment outcome.Conclusions The T-ALL patients with SET-NUP214 fusion gene have some unique cell biological characteristics.SET-NUP214 fusion gene could be used as a molecular marker for MRD monitoring,and which can be used for the follow-up in the course of treatment.

Mixed鄄phenotypic acute leukemia with SET鄄NUP214 fusion gene positive and extramedullary infiltration: report of one case and review of literature / 白血病·淋巴瘤

Objective To investigate the clinical and molecular biological characteristics of mixed_phenotypic acute leukemia (MPAL) with SET_NUP214 fusion gene positive and extramedullary infiltration. Methods The clinical characteristics, diagnosis and treatment of one MPAL patient with SET_NUP214 and extramedullary infiltration who was admitted to Hebei Yanda Ludaopei Hospital in November 2017 were analyzed, and the literature was reviewed. Results The patient was diagnosed as MPAL with extramedullary infiltration. Gene detection found SET exon7_NUP214 exon17 fusion positive accompanied with PHF6, SRSF2 and NRAS mutations. After intensive chemotherapy, the patient achieved complete remission, and then received hematopoietic stem cell transplantation (HSCT), followed by early extramedullary relapse after transplantation, and achieved secondary remission after consolidation chemotherapy. Conclusions MPAL with SET_NUP214 fusion gene positive and extramedullary infiltration has a poor prognosis, and it is easy to relapse. Currently, HSCT is the best available treatment strategy for such patients.