Hematopoietic neoplasms with 9p24/JAK2 rearrangement: a multicenter study

Tang, Guping; Philip, John; Weinberg, Olga K.; Tam, Wayne; Sadigh, Sam; Lake, Jonathan I.; Margolskee, Elizabeth; Rogers, Heesun J.; Miranda, Roberto N.; C, Carlos Bueso-Ramos; Hsi, Eric D.; Orazi, Attilio; Hasserjian, Robert P.; Arber, Daniel A.; Bagg, Adam; Wang, Sa A.

doi:10.1038/s41379-018-0165-9

Cited by 52 publications

(67 citation statements)

References 23 publications

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“…[2][3][4] To date, over 20 JAK2 gene fusion partners have been identified. [2][3][4][5] Herein, we report identification of a novel JAK2 gene fusion partner in a young adult with newly diagnosed B-ALL that we characterized using mate-pair sequencing.…”

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confidence: 99%

“…PCM1-JAK2epositive neoplasms are clinically heterogeneous, and patients may present with myeloproliferative neoplasms, myelodysplastic syndrome, acute myeloid leukemia, and primary or secondary B-and T-cell leukemias and lymphomas. 5 In addition to JAK2 rearrangements, these neoplasms often present with eosinophilia and have been grouped within the category of myeloid/lymphoid neoplasms with eosinophilia and PDGFRA, PDGFRB, and FGFR1 gene rearrangements as a provisional entity in the revised 2017 World Health Organization classification. 1,5 It has been suggested that ETV6-JAK2 and BCR-JAK2 may also be variants of this entity.…”

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confidence: 99%

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

Peterson

Blackburn

Webley

et al. 2019

Mayo Clinic Proceedings

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involvement, and all had improvement in their symptoms. Other patients who had cutaneous and neurological involvement also had symptomatic improvements. The treatment was tolerated well, with only one patient discontinuing therapy because of headache. The performance status improved in 75% of patients, and the median survival for the cohort was 24 months. It is likely that etanercept had an effect on AL amyloidosis, but appropriate response assessment using free light chains and cardiac biomarkers was not available. To our knowledge, this is the first report of a patient with AL amyloidosis and symptoms related to GI involvement responding to therapy with adalimumab. Tumor necrosis factor a could play a role in the pathophysiology of AL amyloidosis. In our patient, diarrhea and severe abdominal pain improved dramatically after receiving a total dose of 80 mg of adalimumab subcutaneously. The effectiveness of this agent could be investigated further in phase I/II trials in patients with refractory AL amyloidosis.

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confidence: 99%

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confidence: 99%

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

Peterson

Blackburn

Webley

et al. 2019

Mayo Clinic Proceedings

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“…In our series, the most notable clinical and morphological features of patients with JAK2 fusion genes included a marked male predominance, lack of hypereosinophilia (≥1.5 × 10 9 /L) in the majority of patients, pathognomonic giant paratrabecular islets of predominantly immature proerythroblasts, 36,37,57 and primary BP or relatively rapid progression to secondary BP in a significant proportion of patients. Patients can achieve CHR and CCR on ruxolitinib but it had to be stopped in all but one patient within the first 3 years, most frequently because of resistance, relapse or progression.…”

Section: Discussionmentioning

confidence: 77%

Response to tyrosine kinase inhibitors in myeloid neoplasms associated with PCM1‐JAK2, BCR‐JAK2 and ETV6‐ABL1 fusion genes

et al. 2020

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We report on 18 patients with myeloid neoplasms and associated tyrosine kinase (TK) fusion genes on treatment with the TK inhibitors (TKI) ruxolitinib (PCM1‐JAK2, n = 8; BCR‐JAK2, n = 1) and imatinib, nilotinib or dasatinib (ETV6‐ABL1, n = 9). On ruxolitinib (median 24 months, range 2‐36 months), a complete hematologic response (CHR) and complete cytogenetic response (CCR) was achieved by five of nine and two of nine patients, respectively. However, ruxolitinib was stopped in eight of nine patients because of primary resistance (n = 3), progression (n = 3) or planned allogeneic stem cell transplantation (allo SCT, n = 2). At a median of 36 months (range 4‐78 months) from diagnosis, five of nine patients are alive: four of six patients after allo SCT and one patient who remains on ruxolitinib. In ETV6‐ABL1 positive patients, a durable CHR was achieved by four of nine patients (imatinib with one of five, nilotinib with two of three, dasatinib with one of one). Because of inadequate efficacy (lack of hematological and/or cytogenetic/molecular response), six of nine patients (imatinib, n = 5; nilotinib, n = 1) were switched to nilotinib or dasatinib. At a median of 23 months (range 3‐60 months) from diagnosis, five of nine patients are in CCR or complete molecular response (nilotinib, n = 2; dasatinib, n = 2; allo SCT, n = 1) while two of nine patients have died. We conclude that (a) responses on ruxolitinib may only be transient in the majority of JAK2 fusion gene positive patients with allo SCT being an important early treatment option, and (b) nilotinib or dasatinib may be more effective than imatinib to induce durable complete remissions in ETV6‐ABL1 positive patients.

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“…Eosinophilia, although helpful in this case, is not universally present in MLN-EGR. Two cases of B-ALLs without eosinophilia were retrospectively found to harbor PCM1-JAK2 in multiple lineages using FISH studies with morphologic correlation, consistent with MLN-PJ in blast crisis (Tang et al 2018). Therefore, assessment for lineage restriction of gene rearrangements to reflect the pathophysiologic difference between B-ALL and MLN-EGR in blast crisis is likely a more robust diagnostic approach and allows the inclusion of MLN-EGR with novel gene fusions.…”

Section: Discussionmentioning

confidence: 99%

“…The hematologic presentations, often with eosinophilia and features of myeloproliferative, myelodysplastic, or overlapping neoplasms, are distinct from B-ALLs. However, transformed B-ALL in MLN-PJ can occur (Reiter et al 2005;Bain and Ahmad 2014;Tang et al 2018). Therefore, separating these two entities can be difficult, especially in cases without a history of myeloid neoplasm.…”

Section: Introductionmentioning

confidence: 99%

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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Hematopoietic neoplasms with 9p24/JAK2 rearrangement: a multicenter study

Cited by 52 publications

References 23 publications

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

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

Response to tyrosine kinase inhibitors in myeloid neoplasms associated with PCM1‐JAK2, BCR‐JAK2 and ETV6‐ABL1 fusion genes

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

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