Identification of novel kinase fusion transcripts in paediatric B cell precursor acute lymphoblastic leukaemia with<i>IKZF1</i>deletion

Mio, Y.; Imamura, Toshihiko; Asai, Daisuke; Kiyokawa, Nobutaka; Nakabayashi, Kazuhiko; Matsumoto, Kenji; Deguchi, Takao; Hashii, Yoshiko; Honda, Yu ko; Hasegawa, Daiichiro; Sasahara, Yoji; Ishii, Mutsuo; Kosaka, Yoshiyuki; Kato, Koji; Shima, Midori; Hori, Hiroki; Yumura‐Yagi, Keiko; Hara, Junichi; Oda, Megumi; Horibe, Keizo; Ichikawa, Hitoshi; Satō, Atsushi

doi:10.1111/bjh.13757

Cited by 25 publications

(15 citation statements)

References 15 publications

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“…27,28 Fusion genes with kinase activity have also been seen in these patients, such as CSF2RA-CRLF2, OFD1-JAK2, and ETV6-NTRK3. 29,30 CRLF2-P2RY8 and JAK2-PPP1R12A were observed in our patient cohort. When tyrosine kinase fusions are identified, these patients are potential candidates for targeted therapies, which may significantly improve outcomes for such higher-risk patients.…”

Section: Discussionsupporting

confidence: 49%

Genome-Wide Single-Nucleotide Polymorphism Array Analysis Improves Prognostication of Acute Lymphoblastic Leukemia/Lymphoma

Wang

Miller

Roulston

et al. 2016

The Journal of Molecular Diagnostics

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Chromosomal abnormalities are important for the risk stratification of acute lymphoblastic leukemia/lymphoma (ALL). However, approximately 30% of pediatric and 50% of adult patients lack abnormalities with clinical relevance by traditional cytogenetic analysis. We integrated cytogenetic, fluorescence in situ hybridization, and whole-genome single-nucleotide polymorphism array results from 60 consecutive clinical ALL cases. By cytogenetic and/or fluorescence in situ hybridization analyses, recurring abnormalities with clinical relevance were observed in 33 B-cell ALL (B-ALL), including t(9;22), hyperdiploidy, KMT2A translocation, ETV6-RUNX1, intrachromosomal amplification of chromosome 21, near haploidy or low hypodiploidy, and t(8;22). Single-nucleotide polymorphism array analysis found additional aberrations with prognostic or therapeutic implication in 21 B-ALL and two T-cell ALL, including IKZF1 deletion, intrachromosomal amplification of chromosome 21 (one case with a normal karyotype), low hypodiploidy (two cases with a normal karyotype), and one case each with fusion genes ETV6-NTRK3, CRLF2-P2RY8, NUP214-ABL1, and SET-NUP214. IKZF1 deletion was noted in nine B-ALL with t(9;22), one B-ALL with t(4;11), five B-ALL with a normal karyotype, and three B-ALL with nonrecurring karyotypic abnormalities. Combining single-nucleotide polymorphism array with chromosome and fluorescence in situ hybridization assays, the detection rate for clinically significant abnormal results increased from 56% to 75%. Whole-genome single-nucleotide polymorphism array analysis detects cytogenetically undetectable clinically significant aberrations and should be routinely applied at diagnosis of ALL.

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Section: Discussionsupporting

confidence: 49%

Genome-Wide Single-Nucleotide Polymorphism Array Analysis Improves Prognostication of Acute Lymphoblastic Leukemia/Lymphoma

Wang

Miller

Roulston

et al. 2016

The Journal of Molecular Diagnostics

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“…13,14,17,61 Fusion of CRLF2 to another PAR1 gene, CSF2RA, has also been described. 43 A recurrent activating CRLF2 F232C point mutation has also been reported, typically in association with CRLF2-Rs. 17 A minority of CRLF2-Rs, particularly P2RY8-CRLF2, occur in cases that do not express the Ph-like ALL signature.…”

Section: Sentinel Molecular Abnormalities In Ph-like Allmentioning

confidence: 99%

“…27,34,45,48,[50][51][52] The amino terminus of JAK2 fusion proteins is encoded by the partner gene fused in-frame to the carboxyl terminal portion of JAK2, including the kinase (TK) domain with or without the upstream pseudokinase domain. 16,27,34,40,42,43,45,48,51,52,68 The expression of JAK2 fusion proteins in vitro results in STAT5 activation and abrogates growth factor dependence in murine lymphoid growth factor-dependent cell lines (eg, Ba/F3), and treatment with ruxolitinib or other JAK2 inhibitors reverses both phenotypes. 24,27,34,42,63,69,70 Rearrangements of the erythropoietin receptor (EPOR-R) involving $4 partner genes (IGH, IGK, LAIR1, and THADA; Table 1) are a recurrent alteration in Ph-like ALL, with an overall frequency of ;1% among B-ALL cases.…”

Section: Figure 2 Crlf2 Rearrangements In Ph-like All (A)mentioning

confidence: 99%

“…77 Other rare kinase fusions in Phlike ALL involve BLNK, DGKH, FGFR1, IL2RB, LYN, PTK2B, TYK2, and RAS pathway genes. 34,43,45,51,52,54,78 The functional properties of rare kinase fusions have generally not been validated, and only FGFR1 has a Food and Drug Administration-approved kinase inhibitor, ponatinib, which was developed for use against the BCR-ABL1 T315I gatekeeper mutation.…”

Section: Abl-class Fusionsmentioning

confidence: 99%

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Philadelphia chromosome–like acute lymphoblastic leukemia

Tasian

Loh

Hunger

2017

Blood

223

219

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Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL), also referred to as --like ALL, is a high-risk subset with a gene expression profile that shares significant overlap with that of Ph-positive (Ph) ALL and is suggestive of activated kinase signaling. Although Ph ALL is defined by - fusion, Ph-like ALL cases contain a variety of genomic alterations that activate kinase and cytokine receptor signaling. These alterations can be grouped into major subclasses that include ABL-class fusions involving ABL1, ABL2, CSF1R, and PDGFRB that phenocopy BCR-ABL1 and alterations of CRLF2, JAK2, and EPOR that activate JAK/STAT signaling. Additional genomic alterations in Ph-like ALL activate other kinases, including BLNK, DGKH, FGFR1, IL2RB, LYN, NTRK3, PDGFRA, PTK2B, TYK2, and the RAS signaling pathway. Recent studies have helped to define the genomic landscape of Ph-like ALL and how it varies across the age spectrum, associated clinical features and outcomes, and genetic risk factors. Preclinical studies and anecdotal reports show that targeted inhibitors of relevant signaling pathways are active in specific Ph-like ALL subsets, and precision medicine trials have been initiated for this high-risk ALL subset.

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“…The formation of alternative splice sites in introns of RNPC3 and JAK2 genes and the additional 22-bp exonized sequence permits the fusion transcript in-frame and retains both the JH2 and JH1 coding sequences in this case. The preservation of JAK2 from exon 13 was reported in one case with OFD1-JAK2 fusion (Yano et al, 2015). The RNPC3 protein is predicted to contain two coiled-coil motifs (Coils v2.1; http://www.ch.embnet.org/softw are/COILS_form.…”

Section: Discussionmentioning

confidence: 99%

Identification of RNPC3 as a novel JAK2 fusion partner gene in B‐acute lymphoblastic leukemia refractory to combination therapy including ruxolitinib

Chen

Wang

Zhang

et al. 2019

Molec Gen & Gen Med

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Background Hematopoietic neoplasms with chromosomal translocations involving JAK2 are rare, and most of them show myeloproliferative neoplasm‐associated features, followed by B‐acute lymphoblastic leukemia (B‐ALL). De novo B‐ALL cases with JAK2 rearrangements are suggested to be appropriately considered as BCR‐ABL1‐like B‐ALL, but its partners varied. Methods Fluorescence in situ hybridization (FISH), RNA sequencing (RNA‐Seq), whole‐genome sequencing, and reverse transcription polymerase chain reaction (RT‐PCR) were performed to identify the pathogenic fusion gene in a 29‐year‐old woman with relapsed B‐ALL and rare t(1;9)(p13;p22) translocation. Results We identified RNPC3 as a new JAK2 fusion partner in the patient. She was treated with a combination of chemotherapy and targeted drug ruxolitinib and chimeric antigen receptor T‐cell therapy, but failed to achieve complete remission. She had no chance to undergo allogeneic hematopoietic stem cell transplantation and died of disease progression 7 months after the initial diagnosis. Her clinical course demonstrated that this novel RNPC3‐JAK2 fusion might portend an unfavorable prognosis. Conclusion This finding adds to the expanding compendium of JAK2 fusions found in B‐ALL and suggests the potential need for a diagnostic FISH analysis as well as RNA‐Seq in the appropriate clinical setting.

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Identification of novel kinase fusion transcripts in paediatric B cell precursor acute lymphoblastic leukaemia withIKZF1deletion

Cited by 25 publications

References 15 publications

Genome-Wide Single-Nucleotide Polymorphism Array Analysis Improves Prognostication of Acute Lymphoblastic Leukemia/Lymphoma

Genome-Wide Single-Nucleotide Polymorphism Array Analysis Improves Prognostication of Acute Lymphoblastic Leukemia/Lymphoma

Philadelphia chromosome–like acute lymphoblastic leukemia

Identification of RNPC3 as a novel JAK2 fusion partner gene in B‐acute lymphoblastic leukemia refractory to combination therapy including ruxolitinib

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