Novel ZEB2-BCL11B Fusion Gene Identified by RNA-Sequencing in Acute Myeloid Leukemia with t(2;14)(q22;q32)

Identification of fusion genes in clinical routine is mostly based on cytogenetics and targeted molecular genetics, such as metaphase karyotyping, FISH and RT-PCR. However, sequencing technologies are becoming more important in clinical routine as processing-time and costs per sample decrease. To evaluate the performance of fusion gene detection by RNA sequencing (RNAseq) compared to standard diagnostic techniques, we analyzed 806 RNA-seq samples from acute myeloid leukemia (AML) patients using two state-of-the-art software tools, namely Arriba and FusionCatcher. RNA-seq detected 90% of fusion events that were reported by routine with high evidence, while samples in which RNA-seq failed to detect fusion genes had overall lower and inhomogeneous sequence coverage. Based on properties of known and unknown fusion events, we developed a workflow with integrated filtering strategies for the identification of robust fusion gene candidates by RNA-seq. Thereby, we detected known recurrent fusion events in 26 cases that were not reported by routine and found discrepancies in evidence for known fusion events between routine and RNA-seq in three cases. Moreover, we identified 157 fusion genes as novel robust candidates and comparison to entries from ChimerDB or Mitelman Database showed novel recurrence of fusion genes in 14 cases. Finally, we detected the novel recurrent fusion gene NRIP1-MIR99AHG resulting from inv(21)(q11.2;q21.1) in nine patients (1.1%) and LTN1-MX1 resulting from inv(21)(q21.3;q22.3) in two patients (0.25%). We demonstrated that NRIP1-MIR99AHG results in overexpression of the 3' region of MIR99AHG and the disruption of the tricistronic miRNA cluster miR-99a/let-7c/miR-125b-2. Interestingly, upregulation of MIR99AHG and deregulation of the miRNA cluster, residing in the MIR99AHG locus, are known mechanism of leukemogenesis in acute megakaryoblastic leukemia. Our findings demonstrate that RNA-seq has a strong potential to improve the systematic detection of fusion genes in clinical applications and provides a valuable tool for fusion discovery.

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Combined use of interferon alpha-1b, interleukin-2, and thalidomide to reverse the AML1-ETO fusion gene in acute myeloid leukemia

Annals of Hematology ◽

10.1007/s00277-021-04621-w ◽

2021 ◽

Author(s):

Ruihua Mi ◽

Lin Chen ◽

Haiping Yang ◽

Yan Zhang ◽

Jia Liu ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Interferon Alpha ◽

Myeloid Leukemia ◽

Clinical Medicine ◽

Fusion Gene ◽

Interleukin 2 ◽

Effective Rate ◽

Dose Administration ◽

Combined Use ◽

Acute Myeloid

AbstractThis study aims to explore the effect of the ITI (interferon alpha-1b, thalidomide, and interleukin-2) regimen on the AML1-ETO fusion gene in patients with t(8;21) acute myeloid leukemia (AML) who were in hematologic remission but positive for the AML1-ETO fusion gene. From September 2014 to November 2020; 20 patients with AML (15 from The Affiliated Cancer Hospital of Zhengzhou University, 4 from The First Affiliated Hospital; and College of Clinical Medicine of Henan University of Science and Technology, and 1 from Anyang District Hospital) with hematological remission but AML1-ETO fusion gene positivity were treated with different doses of the ITI regimen to monitor changes in AML1-ETO fusion gene levels. Twenty patients were treated with a routine dose of the ITI regimen, including 13 males and 7 females. The median patient age was 38 (14–70 years). The fusion gene was negative in 10 patients after 1 (0.5 ~ 8.6) month, significantly decreased in 4 patients after 2.8 (1 ~ 6) months, increased in 4 patients, and unchanged in 2 patients. The 4 patients with elevated levels of the fusion gene were treated with an increased dose of the ITI regimen, and all four patients became negative, for a total effective rate of 90%. The ITI regimen reduces AML1-ETO fusion gene levels in patients with AML who are in hematologic remission but are fusion gene–positive. Improvement was observed in patients’ response to a higher dose administration, and patients tolerated the treatment well.

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The specific distribution pattern of IKZF1 mutation in acute myeloid leukemia

Journal of Hematology & Oncology ◽

10.1186/s13045-020-00972-5 ◽

2020 ◽

Vol 13 (1) ◽

Author(s):

Xiang Zhang ◽

Xuewu Zhang ◽

Xia Li ◽

Yunfei Lv ◽

Yanan Zhu ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Fusion Gene ◽

Lymphoblastic Leukemia ◽

Genetic Alteration ◽

Missense Mutations ◽

Nonsense Mutations ◽

Specific Distribution ◽

Aggressive Clinical Course ◽

Acute Myeloid

Abstract IKZF1 belongs to the IKAROS family of transcription factors, and its deletion/mutation frequently affects acute lymphoblastic leukemia. In acute myeloid leukemia, IKZF1 deletion has been demonstrated recurrent, but whether IKZF1 mutation also exists in AML remained largely unknown. Herein, we analyzed the IKZF1 mutation in AML. In our cohort, the frequency of IKZF1 mutation was 2.6% (5/193), and 5 frameshift/nonsense mutations as well as 2 missense mutations were identified in total. Molecularly, IKZF1 mutation was absent in fusion gene-positive AML, but it was demonstrated as the significant concomitant genetic alteration with SF3B1 or bi-alleleCEBPA mutation in AML. Clinically, two IKZF1, PTPN11 and SF3B1-mutated AML patients exhibited one aggressive clinical course and showed primary resistant to chemotherapy. Furthermore, we confirmed the recurrent IKZF1 mutation in AML with cBioPortal tool from OHSU, TCGA and TARGET studies. Interestingly, OHSU study also showed that SF3B1 mutation was the significant concomitant genetic alteration with IKZF1 mutation, indicating their strong synergy in leukemogenesis. In conclusion, IKZF1 mutation recurrently affected AML.

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TRANSFORMING ACTIVITIES OF THE NUP98-KMT2A FUSION GENE ASSOCIATED WITH MYELODYSPLASIA AND ACUTE MYELOID LEUKEMIA

HemaSphere ◽

10.1097/02014419-201906001-00429 ◽

2019 ◽

Vol 3 ◽

pp. 218

Author(s):

J. N. Fisher ◽

A. Thanasopoulou ◽

S. Juge ◽

A. Tzankov ◽

F. O. Bagger ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Fusion Gene ◽

Acute Myeloid

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A BCR-JAK2 fusion gene as the result of a t(9;22)(p24;q11) in a patient with acute myeloid leukemia

Cancer Genetics and Cytogenetics ◽

10.1016/j.cancergencyto.2008.02.005 ◽

2008 ◽

Vol 183 (2) ◽

pp. 105-108 ◽

Cited By ~ 33

Author(s):

Gabriella Cirmena ◽

Stefania Aliano ◽

Giuseppina Fugazza ◽

Roberto Bruzzone ◽

Anna Garuti ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Fusion Gene ◽

Acute Myeloid

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Sea-Blue Histiocytosis of Bone Marrow in a Patient with t(8;22) Acute Myeloid Leukemia

Case Reports in Oncology ◽

10.1159/000508495 ◽

2020 ◽

Vol 13 (2) ◽

pp. 849-852 ◽

Cited By ~ 1

Author(s):

Osamu Imataki ◽

Makiko Uemura

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Zinc Finger Protein ◽

Fusion Gene ◽

Monocytic Leukemia ◽

Non Hodgkin Lymphoma ◽

Old Japanese ◽

Characteristic Features ◽

Acute Myeloid

An 80-year-old Japanese male was treated with chemotherapy consisting of cyclophosphamide, doxorubicin, vincristine, and prednisolone, for non-Hodgkin lymphoma. Nine months after the chemotherapy, he was diagnosed with acute myeloid leukemia (AML) (M4) with translocation 8p11 and 22q13. The patient bone marrow indicated a remarkable degree of sea-blue histiocytosis. His disease was aggressive, and he died of the disease. Sea-blue histiocytes are macrophages harboring blue vacuoles and granular deposition, which results from the phagocytosis of dead cells and the subsequent deposition of phospholipids. AML with the t(8; 22) (p11; q13) translocation is a rare subtype of AML, which is a rare translocation with a prevalence of less than 1.0% among all AML cases. The oncogenesis of t(8; 22) (p11; q13) is caused by the fusion protein monocytic leukemia zinc finger protein (MOZ) and transcription factor p300. MOZ can be fused to various translocation targets including CBT, TIF2, and p300, corresponding to t(8; 16), inv(8), and t(8; 22), respectively. This subgroup of AML reveals the hallmarks of the disease, including monocytic arrest and erythro/hemophagocytosis by blasts. A substantial proportion of the AML M4/M5 subtype harboring MOZ as an aberrant fusion gene represents erythrophagocytosis. Although rare, t(8; 22) is very specific to the AML M4/M5 subtype and seems to represent sea-blue histiocytosis as one of the characteristic features of monocytic AML with macrophage activation. Thus, sea-blue histiocytes are considered to be one of hallmarks in monocytic AML with MOZ translocation.

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