Spectrum of somatic mutations detected by targeted next-generation sequencing and their prognostic significance in adult patients with acute lymphoblastic leukemia

Feng, Juan; Li, Yan; Jia, Yujiao; Fang, Qiuyun; Gong, Xiaoyuan; Dong, Xiaobao; Ru, Kun; Li, Qinghua; Zhao, Xingli; Liu, Kaiqi; Wang, Min; Tian, Zheng; Jia, Yannan; Wang, Ying; Lin, Dong; Wei, Hui; Tang, Kejing; Mi, Yingchang; Wang, Jianxiang

doi:10.1186/s13045-017-0431-1

Cited by 29 publications

(31 citation statements)

References 9 publications

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“…Clinically, some sequencing studies have associated the RAS activating mutations with poor outcomes. Therefore, the presence of these mutations has been recognized as an independent predictor of poor outcome in childhood KMT2A(MLL1) -r ALL and the presence of PTPN11 mutations has been associated with a good prognosis in adult B-ALL patients [ 46 , 47 ]. Not only do RAS mutation-positive patients have a high risk of relapse but also the prognosis for RAS mutation-negative patients remains far from favorable.…”

Section: The Mutational Landscape In Signaling Pathways Involved Imentioning

confidence: 99%

New Challenges in Targeting Signaling Pathways in Acute Lymphoblastic Leukemia by NGS Approaches: An Update

Montaño

Forero-Castro

Marchena-Mendoza

et al. 2018

Cancers

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The identification and study of genetic alterations involved in various signaling pathways associated with the pathogenesis of acute lymphoblastic leukemia (ALL) and the application of recent next-generation sequencing (NGS) in the identification of these lesions not only broaden our understanding of the involvement of various genetic alterations in the pathogenesis of the disease but also identify new therapeutic targets for future clinical trials. The present review describes the main deletions, amplifications, sequence mutations, epigenetic lesions, and new structural DNA rearrangements detected by NGS in B-ALL and T-ALL and their clinical importance for therapeutic procedures. We reviewed the molecular basis of pathways including transcriptional regulation, lymphoid differentiation and development, TP53 and the cell cycle, RAS signaling, JAK/STAT, NOTCH, PI3K/AKT/mTOR, Wnt/β-catenin signaling, chromatin structure modifiers, and epigenetic regulators. The implementation of NGS strategies has enabled important mutated genes in each pathway, their associations with the genetic subtypes of ALL, and their outcomes, which will be described further. We also discuss classic and new cryptic DNA rearrangements in ALL identified by mRNA-seq strategies. Novel cooperative abnormalities in ALL could be key prognostic and/or predictive biomarkers for selecting the best frontline treatment and for developing therapies after the first relapse or refractory disease.

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Section: The Mutational Landscape In Signaling Pathways Involved Imentioning

confidence: 99%

New Challenges in Targeting Signaling Pathways in Acute Lymphoblastic Leukemia by NGS Approaches: An Update

Montaño

Forero-Castro

Marchena-Mendoza

et al. 2018

Cancers

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“…Cytogenetic studies demonstrated a complex karyotype similar to that of his original leukemia. FLT3-ITD PCR was negative but extended mutational testing—not previously performed—revealed mutations in FBXW7, NOTCH1, and EZH2, all of which are recurrently mutated in T-ALL [ 8 ]. Additionally, bone marrow chimerism studies showed for the first time a decline in CD3 donor chimerism from 100% to 91%.…”

Section: Case Presentationmentioning

confidence: 99%

Venetoclax in Combination with Decitabine for Relapsed T-Cell Acute Lymphoblastic Leukemia after Allogeneic Hematopoietic Cell Transplant

Rahmat

Nguyen

Abdulhaq

et al. 2018

Case Reports in Hematology

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Long-term disease-free survival in adults with T-cell acute lymphoblastic leukemia (T-ALL) remains poor, particularly after relapse, with few available salvage options. Preclinical data suggest that inhibition of the antiapoptotic protein BCL-2 (B-cell lymphoma 2) either alone or in combination with other agents, may be a unique therapeutic approach for the treatment of T-ALL. We present a case of a young male with T-ALL, relapsed after allogeneic hematopoietic stem cell transplant, who achieved a second complete remission following salvage therapy with combined venetoclax and decitabine. Assessment of measurable residual disease by next generation sequencing showed no evidence of residual disease of a sensitivity of 1 × 10−6. While the combination of venetoclax and hypomethylating agents has shown promise in the treatment of relapsed/refractory AML, and to our knowledge, this is the first report of this combination demonstrating clinical activity in relapsed/refractory T-ALL.

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“…1 ): 46, XX, t(1;9)(p22;q34)[9]/46; XX, t(1;9)(p22;q34),-2,+22[1]/45, XX, t(1;9)(p22;q34),-21[1]/46, XX[9]. Somatic mutations were detected by targeted next-generation sequencing ( 18 , 19 ): The patient was negative for FLT3/ITD, FLT3/TKD, C-KIT Exon 8, C-KIT D816, CEBPα/TAD, CEBPα/BZIP, DNMT3A/ZNF and DNMT3A/Mtase mutations. In order to identify the specific fusion gene formed by the chromosomal abnormalities in the patient, transcriptome sequencing (RNA-seq) was performed on the patient's bone marrow mononuclear cells and peripheral blood cells in the complete remission (CR) state.…”

Section: Case Reportmentioning

confidence: 99%

A novel variant translocation (1;9)(p22;q34) resulting in a DEK/NUP214 fusion gene in a patient with acute myeloid leukemia: A case report

Hao

Zhang

et al. 2017

Oncol Lett

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The present case report describes a 46-year-old female patient diagnosed with M4 acute myeloid leukemia (AML), accompanied with a t(1;9)(p22;q34) chromosomal abnormality. Transcriptome sequencing identified a DEK proto-oncogene (DEK)/nucleoporin (NUP)214 fusion gene, which results from the t(6;9)(p23;q34) chromosomal translocation. Polymerase chain reaction analysis and fluorescence in situ hybridization were used to verify the existence of the DEK/NUP214 fusion gene. Few patients with AML with the t(6;9)(p23;q34) chromosomal translocation have been reported to have other chromosomal or karyotype changes. To our knowledge, no AML patient with the DEK/NUP214fusion gene but without the classic t(6;9)(p23;q34) translocations had been reported until now. The prognosis of AML cases with the DEK/NUP214 fusion gene is poor. The rate of complete remission is ~65% (71% in children, 58% in adult patients), while the estimated 5-year survival rate is 28% for children and 9% for adults. The 2008 revision of World Health Organization classification have defined the DEK/NUP214 mutation as a recurrent genetic abnormality of AML. The overall survival of the patient in the current report was ~29 months, and they relapsed twice. To the best of our knowledge, this is the first report of at(1;9)(p22;q34) variant translocation that results in expression of the DEK/NUP214 fusion gene.

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Spectrum of somatic mutations detected by targeted next-generation sequencing and their prognostic significance in adult patients with acute lymphoblastic leukemia

Cited by 29 publications

References 9 publications

New Challenges in Targeting Signaling Pathways in Acute Lymphoblastic Leukemia by NGS Approaches: An Update

New Challenges in Targeting Signaling Pathways in Acute Lymphoblastic Leukemia by NGS Approaches: An Update

Venetoclax in Combination with Decitabine for Relapsed T-Cell Acute Lymphoblastic Leukemia after Allogeneic Hematopoietic Cell Transplant

A novel variant translocation (1;9)(p22;q34) resulting in a DEK/NUP214 fusion gene in a patient with acute myeloid leukemia: A case report

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