Acquisition of genomic events leading to lymphoblastic transformation in a rare case of myeloproliferative neoplasm with <i>BCR–JAK2</i> fusion transcript

Duployez, Nicolas; Nibourel, Olivier; Ducourneau, Benoît; Grardel, Nathalie; Boyer, Thomas D.; Bories, Claire; Darre, Stéphane; Coiteux, Valérie; Berthon, Céline; Preudhomme, Claude; Roche‐Lestienne, Catherine

doi:10.1111/ejh.12752

Cited by 8 publications

(14 citation statements)

References 5 publications

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“…reported a patient with myeloproliferative neoplasm who progressed to blast crisis upon acquisition of biallelic IKZF1 deletions, as well as EBF1 and CDKN2A/B deletions. In this case, IKZF1 deletion involved its surrounding genes, from VWC2 until COBL [ 22 ]. Furthermore, Gonzalez-Gonzalez et al .…”

Section: Discussionmentioning

confidence: 99%

COBL is a novel hotspot for IKZF1 deletions in childhood acute lymphoblastic leukemia

et al. 2016

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IKZF1 deletion (ΔIKZF1) is an important predictor of relapse in childhood B-cell precursor acute lymphoblastic leukemia. Because of its clinical importance, we previously mapped breakpoints of intragenic deletions and developed a multiplex PCR assay to detect recurrent intragenic ΔIKZF1. Since the multiplex PCR was not able to detect complete deletions (IKZF1 Δ1-8), which account for ~30% of all ΔIKZF1, we aimed at investigating the genomic scenery of IKZF1 Δ1-8. Six samples of cases with IKZF1 Δ1-8 were analyzed by microarray assay, which identified monosomy 7, isochromosome 7q, and large interstitial deletions presenting breakpoints within COBL gene. Then, we established a multiplex ligation-probe amplification (MLPA) assay and screened copy number alterations within chromosome 7 in 43 diagnostic samples with IKZF1 Δ1-8. Our results revealed that monosomy and large interstitial deletions within chromosome 7 are the main causes of IKZF1 Δ1-8. Detailed analysis using long distance inverse PCR showed that six patients (16%) had large interstitial deletions starting within intronic regions of COBL at diagnosis, which is ~611 Kb downstream of IKZF1, suggesting that COBL is a hotspot for ΔIKZF1. We also investigated a series of 25 intragenic deletions (Δ2–8, Δ3–8 or Δ4–8) and 24 relapsed samples, and found one IKZF1-COBL tail-to-tail fusion, thus supporting that COBL is a novel hotspot for ΔIKZF1. Finally, using RIC score methodology, we show that breakpoint sequences of IKZF1 Δ1-8 are not analog to RAG-recognition sites, suggesting a different mechanism of error promotion than that suggested for intragenic ΔIKZF1.

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Section: Discussionmentioning

confidence: 99%

COBL is a novel hotspot for IKZF1 deletions in childhood acute lymphoblastic leukemia

et al. 2016

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“…67,71 The clinical course of JAK2-rearranged neoplasms is aggressive, with rapid progression from chronic phase disease to AML, and more rarely to lymphoid blast phase, which has been associated with acquisition of biallelic IKZF1 alteration as well as EBF1 and CDKN2A/B codeletions. 77 Patients may also present as de novo acute leukemia, with myeloid being more common than lymphoid origin. 73 The involvement of both myeloid and lymphoid lineages demonstrates that PCM1-JAK2-positive neoplasms originate from an early pluripotent hematopoietic progenitor or stem cell.…”

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confidence: 99%

Myeloid neoplasms with eosinophilia

Reiter

Gotlib

2017

Blood

222

274

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Molecular diagnostics has generated substantial dividends in dissecting the genetic basis of myeloid neoplasms with eosinophilia. The family of diseases generated by dysregulated fusion tyrosine kinase (TK) genes is recognized by the World Health Organization (WHO) category, “Myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1, or with PCM1-JAK2.” In addition to myeloproliferative neoplasms (MPN), these patients can present with myelodysplastic syndrome/MPN, as well as de novo or secondary mixed-phenotype leukemias or lymphomas. Eosinophilia is a common, but not invariable, feature of these diseases. The natural history of PDGFRA- and PDGFRB-rearranged neoplasms has been dramatically altered by imatinib. In contrast, patients with FGFR1 and JAK2 fusion TK genes exhibit a more aggressive course and variable sensitivity to current TK inhibitors, and in most cases, long-term disease-free survival may only be achievable with allogeneic hematopoietic stem cell transplantation. Similar poor prognosis outcomes may be observed with rearrangements of FLT3 or ABL1 (eg, both of which commonly partner with ETV6), and further investigation is needed to validate their inclusion in the current WHO-defined group of eosinophilia-associated TK fusion-driven neoplasms. The diagnosis chronic eosinophilic leukemia, not otherwise specified (CEL, NOS) is assigned to patients with MPN with eosinophilia and nonspecific cytogenetic/molecular abnormalities and/or increased myeloblasts. Myeloid mutation panels have identified somatic variants in patients with a provisional diagnosis of hypereosinophilia of undetermined significance, reclassifying some of these cases as eosinophilia-associated neoplasms. Looking forward, one of the many challenges will be how to use the results of molecular profiling to guide prognosis and selection of actionable therapeutic targets.

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“…The median age of the 49 patients with JAK2 fusion genes was 50 years (range 22‐84 years) with a marked male predominance (39/49, 80%). Overall, 17 of49 (35%) patients were diagnosed with primary BP (n = 11; myeloid BP/AML, n = 7; lymphoid BP/ALL; n = 4) or progressed to secondary BP (n = 6; myeloid, n = 5; lymphoid, n = 1) at a median of 20 months (range 7‐72 months) from diagnosis 8,14,41,50 . Treatment with ruxolitinib for 16, 26 and 46 months, respectively, has only been reported in three further patients who achieved CHR (n = 3) or CCR (n = 2) 12‐15 .…”

Section: Resultsmentioning

confidence: 99%

“…With censoring for allo SCT, OS was not different for patients treated with or without ruxolitinib (Figure 2). An allo SCT was performed in 18/49 (37%) patients 8,31‐33,36‐38,42,46,49,50,52,56 . Two further patients underwent an autologous SCT (auto SCT) after intensive chemotherapy for ALL 33,56 .…”

Section: Resultsmentioning

confidence: 99%

“…We therefore sought to evaluate the clinical characteristics and response to various TKI in 18 patients with myeloid neoplasms and associated PCM1‐JAK2 , BCR‐JAK2 or ETV6‐ABL1 fusion genes. In an extended analysis, we integrated our data into the reports of 40 patients with JAK2 fusion genes ( PCM1‐JAK2 , n = 28) 8,9,12‐15,28‐40 or BCR‐JAK2 (n = 12) 41‐52 and 14 patients with TKI‐treated ETV6‐ABL1 positive chronic myeloid neoplasms 16‐27,53,54 . This analysis provides a comprehensive overview of responses to TKIs in patients with these rare fusions.…”

Section: Introductionmentioning

confidence: 99%

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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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Acquisition of genomic events leading to lymphoblastic transformation in a rare case of myeloproliferative neoplasm with BCR–JAK2 fusion transcript

Cited by 8 publications

References 5 publications

COBL is a novel hotspot for IKZF1 deletions in childhood acute lymphoblastic leukemia

COBL is a novel hotspot for IKZF1 deletions in childhood acute lymphoblastic leukemia

Myeloid neoplasms with eosinophilia

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

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