Identification of a Novel ZBTB20-JAK2 Fusion by Mate-Pair Sequencing in a Young Adult With B-Lymphoblastic Leukemia/Lymphoma

Peterson, Jess F.; Blackburn, Patrick R.; Webley, Matthew; Pearce, Kathryn E.; Williamson, Cynthia M.; Vasmatzis, George; Smadbeck, James B.; Bieliauskas, Shannon L.; Reichard, Kaaren K.; Ketterling, Rhett P.; Baughn, Linda B.; Greipp, Patricia T.

doi:10.1016/j.mayocp.2019.04.030

Cited by 8 publications

(6 citation statements)

References 11 publications

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“…A different group has reported the detection of ZBTB20-JAK2 fusion from the same patient using mate-pair sequencing (Peterson et al 2019). Their report offers a different level of information and nicely complements our findings.…”

Section: Discussionsupporting

confidence: 76%

The diagnostic challenges and clinical course of a myeloid/lymphoid neoplasm with eosinophilia and ZBTB20-JAK2 gene fusion presenting as B-lymphoblastic leukemia

Lee

Pfau

Choi

et al. 2020

Cold Spring Harb Mol Case Stud

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We report the diagnostic challenges and the clinical course of a patient with an extraordinary presentation of B-lymphoblastic leukemia (B-ALL) with eosinophilia. We identified a novel ZBTB20-JAK2 gene fusion as a chimeric RNA transcript using the Archer platform. This gene fusion from the same patient was recently identified by Peterson et al. (2019) at the genomic level using a different sequencing technology platform. The configuration of this gene fusion predicts the production of a kinase-activating JAK2 fusion protein, which would normally lead to a diagnosis of Philadelphia chromosome-like BALL (Ph-like BALL). However, the unusual presentation of eosinophilia led us to demonstrate the presence of this gene fusion in nonlymphoid hematopoietic cells by fluorescence in situ hybridization (FISH) studies with morphologic correlation. Therefore, we believe this disease, in fact, represents blast crisis arising from an underlying myeloid neoplasm with JAK2 rearrangements. This case illustrates the difficulty in differentiating Ph-like BALL and myeloid/lymphoid neoplasm with eosinophilia and gene rearrangements (MLN-EGR) in blast crisis. As currently defined, the diagnosis of MLN-EGR relies on the hematologic presentations and the identification of marker gene fusions (including PCM1-JAK2, ETV6-JAK2, and BCR-JAK2). However, these same gene fusions, when limited to B-lymphoblasts, also define Ph-like BALL. Yet, our case does not conform to either condition. Therefore, the assessment for lineage restriction of gene rearrangements to reflect the pathophysiologic difference between BALL and MLN-EGR in blast crisis is likely a more robust diagnostic approach and allows the inclusion of MLN-EGR with novel gene fusions.

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Section: Discussionsupporting

confidence: 76%

The diagnostic challenges and clinical course of a myeloid/lymphoid neoplasm with eosinophilia and ZBTB20-JAK2 gene fusion presenting as B-lymphoblastic leukemia

Lee

Pfau

Choi

et al. 2020

Cold Spring Harb Mol Case Stud

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“…The first case of constitutive activation of JAK2 signaling due to JAK2 fusion with partner TEL (ETV6) in T-ALL/LBL was reported in 1997 [4]. Similarly, a novel ZBTB20-JAK2 fusion was recently reported in a young adult with a newly diagnosed B-ALL with eosinophilia [12]. Our case is a JAK2 fusion with a novel partner TBL1XR1 in a T-ALL/LBL patient with a significant increase in the absolute count of eosinophils.…”

Section: Discussionsupporting

confidence: 49%

“…Because the cytogenetic location of the TBL1XR1 gene is 3q26.32 (https://ghr.nlm.nih.gov/gene/ TBL1XR1), this fusion gene is consistent with the cytogenetic finding of t(3;9)(q26;p24) translocation. We hypothesize that TBL1XR1-JAK2 gene fusion functions like all other JAK2 chimeric fusions, such as PCM1-JAK2 and TEL-JAK2 [4,12]. These hybrid proteins cause constitutive activation of the JAK-STAT5 and PI3K signaling pathways, which can regulate cell survival, growth, and differentiation.…”

Section: Discussionmentioning

confidence: 99%

TBL1XR1-JAK2: a novel fusion in a pediatric T cell acute lymphoblastic leukemia patient with increased absolute eosinophil count

et al. 2020

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T-lymphoblastic leukemia/lymphoma (T-ALL/LBL) with any JAK2 gene fusion is rarely reported. Here, we report a case of T-ALL with a novel TBL1XR1-JAK2 gene fusion in a 5-year-old boy. His lab showed a high white blood cell count, mild anemia, moderate thrombocytopenia, and concurrently increased eosinophils (absolute eosinophil count: 4 × 10^9/L). Peripheral blood and bone marrow aspirate smears showed > 90% mononucleated blasts. Flow cytometry on peripheral blood revealed a large blast population positive for CD2, surface CD3 (< 25%), CD10 (50%), CD5, CD7, CD4, CD8, TdT, CD1a (60%), and CD45. Conventional karyotype analysis showed t(3;9)(q26;p24) and t(11;14)(p13;q11.2)/TCRD-LMO2. Next-generation sequencing (NGS) identified a novel TBL1XR1-JAK2 gene fusion in a sequencing depth of 180 × by RNAseq, FBXW7 R465H mutation, and loss of exons 2-3 of CDKN2A/B by DNAseq. Follow-up bone marrow aspirate on day-28 post-induction therapy revealed no morphologic evidence of residual leukemia. We believe that the TBL1XR1-JAK2 fusion may behave in a similar functional manner to the PCM1-JAK2 fusion gene and constitutes a new variant of this family and a potential target of tyrosine kinase inhibitor (TKI) therapy.

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“…ZBTB20-JAK2, ZBTB46-JAK2). 40,41 To date, more than 20 different partner genes have been identified with JAK2 fusions in Ph-like ALL; all JAK2 fusions conserved an intact kinase domain and conferred constitutive JAK2 kinase activation. 41 Another advantage of RNA-seq that we demonstrate is the ability to identify clonal mutations at diagnosis that may carry prognostic and therapeutic impact.…”

Section: Discussionmentioning

confidence: 99%

Whole-transcriptome analysis in acute lymphoblastic leukemia: a report from the DFCI ALL Consortium Protocol 16-001

et al. 2022

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The molecular hallmark of childhood ALL is characterized by recurrent, prognostic genetic alterations, many of which are cryptic by conventional cytogenetics. RNA-seq is a powerful next-generation sequencing technology with the ability to simultaneously identify cryptic gene rearrangements, sequence mutations and gene expression profiles in a single assay. We examined the feasibility and utility of incorporating RNA-seq into a prospective multi-center phase 3 clinical trial for children with newly-diagnosed ALL. Patients enrolled on the DFCI ALL Consortium Protocol 16-001 who consented to optional studies and had available material underwent RNA-seq. RNA-seq was performed in 173 ALL patients. RNA-seq identified at least one alteration in 157 (91%) patients. Fusion detection was 100% concordant with results obtained from conventional cytogenetic analyses. An additional 56 gene fusions were identified by RNA-seq, many of which confer prognostic or therapeutic significance. Gene expression profiling enabled further molecular classification into the following B-ALL subgroups: High hyperdiploid (n=36), ETV6-RUNX1/-like (n=31), TCF3-PBX1 (n=7), KMT2A-rearranged (n=5), iAMP21 (n=1), hypodiploid (n=1), BCR-ABL1/-like (n=16), DUX4-rearranged (n=11), PAX5 alterations (n=11), PAX5 P80R (n=1), ZNF384-rearranged (n=4), NUTM1-rearranged (n=1), MEF2D-rearranged (n=1) and Others (n=10). RNA-seq identified 141 nonsynonymous mutations in 93 (54%) patients; the most frequent were RAS-MAPK pathway mutations. Among 79 patients with both low-density array and RNA-seq data for the Ph-like gene signature prediction, results were concordant in 74 (94%) patients. In conclusion, RNA-seq identified several clinically-relevant genetic alterations not detected by conventional methods, supporting the integration of this technology in frontline pediatric ALL trials.

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Identification of a Novel ZBTB20-JAK2 Fusion by Mate-Pair Sequencing in a Young Adult With B-Lymphoblastic Leukemia/Lymphoma

Cited by 8 publications

References 11 publications

The diagnostic challenges and clinical course of a myeloid/lymphoid neoplasm with eosinophilia and ZBTB20-JAK2 gene fusion presenting as B-lymphoblastic leukemia

The diagnostic challenges and clinical course of a myeloid/lymphoid neoplasm with eosinophilia and ZBTB20-JAK2 gene fusion presenting as B-lymphoblastic leukemia

TBL1XR1-JAK2: a novel fusion in a pediatric T cell acute lymphoblastic leukemia patient with increased absolute eosinophil count

Whole-transcriptome analysis in acute lymphoblastic leukemia: a report from the DFCI ALL Consortium Protocol 16-001

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