Recurrent SPI1 (PU.1) fusions in high-risk pediatric T cell acute lymphoblastic leukemia

Seki, Masafumi; Kimura, Shunsuke; Isobe, Tomoya; Yoshida, Kenichi; Ueno, Hikaru; Nakajima‐Takagi, Yaeko; Wang, Changshan; Lin, Lin; Kon, Ayana; Suzuki, Hiromichi; Shiozawa, Yusuke; Kataoka, Keisuke; Fujii, Yoichi; Shiraishi, Yuichi; Chiba, Kenichi; Tanaka, Hiroko; Shimamura, Teppei; Masuda, Kyoko; Kawamoto, Hiroshi; Ohki, Kentaro; Kato, Motohiro; Arakawa, Yuki; Koh, Katsuyoshi; Hanada, Ryoji; Moritake, Hiroshi; Akiyama, Masaharu; Kobayashi, Ryōji; Deguchi, Takao; Hashii, Yoshiko; Imamura, Toshihiko; Satō, Atsushi; Kiyokawa, Nobutaka; Oka, Akira; Hayashi, Yasuhide; Takagi, Motoki; Manabe, Atsushi; Ohara, Akira; Horibe, Keizo; Sanada, Masashi; Iwama, Atsushi; Mano, Hiroyuki; Miyano, Satoru; Ogawa, Seishi; Takita, Junko

doi:10.1038/ng.3900

Cited by 112 publications

(149 citation statements)

References 63 publications

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“…The integrated analysis of gene alterations in two recent series of pediatric T-ALL provided an enlarged view of the genomic landscape in this heterogenous disease (20,23). However, complex interplay of gene fusions, sequence abnormalities, and transcriptional expression profiles, especially in adult cases, needs to be further addressed to refine the current model of T-ALL leukemogenesis and to reveal potential new biomarkers and therapeutic targets.…”

mentioning

confidence: 99%

Identification of fusion genes and characterization of transcriptome features in T-cell acute lymphoblastic leukemia

Chen

Jiang

Zhong

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

116

138

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T-cell acute lymphoblastic leukemia (T-ALL) is a clonal malignancy of immature T cells. Recently, the next-generation sequencing approach has allowed systematic identification of molecular features in pediatric T-ALL. Here, by performing RNA-sequencing and other genomewide analysis, we investigated the genomic landscape in 61 adult and 69 pediatric T-ALL cases. Thirty-six distinct gene fusion transcripts were identified, with SET-NUP214 being highly related to adult cases. Among 18 previously unknown fusions, ZBTB16-ABL1, TRA-SALL2, and involvement of NKX2-1 were recurrent events. ZBTB16-ABL1 functioned as a leukemogenic driver and responded to the effect of tyrosine kinase inhibitors. Among 48 genes with mutation rates >3%, 6 were newly found in T-ALL. An aberrantly overexpressed short mRNA transcript of the SLC17A9 gene was revealed in most cases with overexpressed TAL1, which predicted a poor prognosis in the adult group. Up-regulation of HOXA, MEF2C, and LYL1 was often present in adult cases, while TAL1 overexpression was detected mainly in the pediatric group. Although most gene fusions were mutually exclusive, they coexisted with gene mutations. These genetic abnormalities were correlated with deregulated gene expression markers in three subgroups. This study may further enrich the current knowledge of T-ALL molecular pathogenesis.

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mentioning

confidence: 99%

Identification of fusion genes and characterization of transcriptome features in T-cell acute lymphoblastic leukemia

Chen

Jiang

Zhong

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

116

138

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“…2,9,10,[14][15][16] Detailed analysis of our next-generation sequencing data 9,10,18 revealed that 14 of 41 JAK3-mutant T-ALLs have either a homozygous JAK3 mutation or 2 different JAK3 mutations ( Figure 1A). In a recently published exome sequencing study, 3 of 20 JAK3-mutant T-ALL patient cases were reported to harbor 2 JAK3 mutations.…”

Section: Resultsmentioning

confidence: 99%

“…11,12 Between 10% and 16% of patients with T-ALL carry at least 1 mutation in JAK3. 2,9,10,[14][15][16] A more detailed analysis presented here shows that up to a third of these patient cases harbor a second JAK3 mutation, and we investigated the biological significance of having multiple JAK3 mutations.…”

Section: Introductionmentioning

confidence: 99%

Mutant JAK3 signaling is increased by loss of wild-type JAK3 or by acquisition of secondary JAK3 mutations in T-ALL

Degryse

Bornschein

Bock

et al. 2018

Blood

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K E Y P O I N T Sl One-third of T-ALL cases with JAK3 mutation harbor 2 JAK3 mutations.l Double JAK3 mutants show stronger signaling than single JAK3 mutants.The Janus kinase 3 (JAK3) tyrosine kinase is mutated in 10% to 16% of T-cell acute lymphoblastic leukemia (T-ALL) cases. JAK3 mutants induce constitutive JAK/STAT signaling and cause leukemia when expressed in the bone marrow cells of mice. Surprisingly, we observed that one third of JAK3-mutant T-ALL cases harbor 2 JAK3 mutations, some of which are monoallelic and others that are biallelic. Our data suggest that wild-type JAK3 competes with mutant JAK3 (M511I) for binding to the common g chain and thereby suppresses its oncogenic potential. We demonstrate that JAK3 (M511I) can increase its limited oncogenic potential through the acquisition of an additional mutation in the mutant JAK3 allele. These double JAK3 mutants show increased STAT5 activation and increased potential to transform primary mouse pro-T cells to interleukin-7-independent growth and were not affected by wild-type JAK3 expression. These data extend our insight into the oncogenic properties of JAK3 mutations and provide an explanation of why progression of JAK3-mutant T-ALL cases can be associated with the accumulation of additional JAK3 mutations. (Blood. 2018;131(4):421-425)

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“…Centriolar assembly protein–T‐cell acute lymphocytic leukemia 1 (STIL‐TAL1), caused by the deletion of 1p32, and mixed lineage leukemia–super elongation complex subunit (MLL‐MLLT1), caused by t(11;19), are observed recurrently in T‐ALL, although these fusions are not used for treatment stratification. Recently, recurrent gene fusions involving Spi‐1 proto‐oncogene ( SPI1 ) were identified in 3.9% of 121 pediatric T‐ALL cases investigated, which was associated with poor overall survival …”

Section: Recent Advances In Molecular Biology Of Pediatric Allmentioning

confidence: 99%

Treatment and biology of pediatric acute lymphoblastic leukemia

Kato

Manabe

2018

Pediatrics International

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Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. In the past ALL was intractable but now the survival probability is as high as 80-90%. Improved supportive care, treatment stratification based on relapse risk, biological features of leukemic cells, and optimization of treatment regimens by nationwide and international collaboration have contributed to this dramatic improvement. While including traditional risk factors (e.g. age and leukocyte count at diagnosis), the treatment has been modified based on biological characteristics (aneuploidy and translocation) and treatment response (assessed by minimal residual disease). Treatment for pediatric ALL typically consists of induction therapy with steroids, vincristine, and asparaginase with or without anthracycline, followed by multi-agent consolidation including high-dose methotrexate and re-induction therapy. After consolidation, less intensive maintenance therapy is required for 1-2 years to maintain event-free survival. Recently, using advanced genomic analysis technology, novel sentinel genomic alterations that may provide more precise stratification or therapeutic targets, were identified. Moreover, in the last decade germline variations have been recognized as similarly important contributors to understanding the etiology and sensitivity of ALL to treatment. A more individualized approach based on genomic features (somatic and germline) and treatment response, the introduction of newly developed agents such as molecular targeted drugs or immunotherapy, and social support including long-term follow up are required for further improvement.Key words acute lymphoblastic leukemia, biology, clinical trial, treatment.Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy and is newly diagnosed in approximately 500 children in Japan annually. A slight male predominance (approx. 1.2-fold higher in boys) has been observed, with a peak incidence at 1-4 years of age. 1 Survival rates were poor 50 years ago, and leukemia was considered to be an intractable disease. Most recent clinical trials, however, have achieved an overall survival probability of 80-90%. The main contributors to this dramatic improvement are the availability of better supportive care, treatment stratification based on relapse risk and the biological features of leukemic cells, and the accumulation of evidence uncovered by clinical trials through nationwide and international collaboration. We herein review the history, current status, and future prospects for the treatment of pediatric ALL, focusing on interventions and biology while excluding infant ALL and relapsed ALL, which have been reported on elsewhere. 2,3

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Recurrent SPI1 (PU.1) fusions in high-risk pediatric T cell acute lymphoblastic leukemia

Cited by 112 publications

References 63 publications

Identification of fusion genes and characterization of transcriptome features in T-cell acute lymphoblastic leukemia

Identification of fusion genes and characterization of transcriptome features in T-cell acute lymphoblastic leukemia

Mutant JAK3 signaling is increased by loss of wild-type JAK3 or by acquisition of secondary JAK3 mutations in T-ALL

Treatment and biology of pediatric acute lymphoblastic leukemia

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