NDEL1-PDGFRB fusion gene in a myeloid malignancy with eosinophilia associated with resistance to tyrosine kinase inhibitors

Byrgazov, Konstantin; Kastner, Renate; Górna, Maria W.; Hoermann, Gregor; Koenig, Margit; Lucini, Chantal; Ulreich, Raphael; Benesch, Martin; Strenger, Volker; Lackner, Herwig; Schwinger, Wolfgang; Sovinz, Petra; Haas, Oskar A.; Heuvel‐Eibrink, MM van den; Niemeyer, C.; Hantschel, Oliver; Valent, Peter; Superti‐Furga, Giulio; Urban, Christian; Dworzak, Michael; Lion, Thomas

doi:10.1038/leu.2016.250

Cited by 10 publications

(8 citation statements)

References 18 publications

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“…Similar to FIP1L1-PDGFRA positive myeloid neoplasms, special attention should certainly be paid to involvement of the heart with its potentially life-threatening complications. [10][11][12] Rapid and durable complete clinical and hematological remissions on imatinib were observed in all reported chronic phase patients within median 2 months. Cytogenetic analysis for confirmation of CCR and fusion gene specific RT-PCR for confirmation of CMR was not performed in all patients.…”

Section: Discussionmentioning

confidence: 92%

“…However, three patients in blast phase (patient #1, #4 an #5) and eight patients in chronic phase have been previously published separately. [3][4][11][12][13][14] In peripheral blood (PB), significant eosinophilia ≥0.5x10 9 /L was absent in 4/19 (21%) and ≥1.5x10 /L in 8/19 (42%) patients, respectively (Table 1). All patients in blast phase had a short history of persistent eosinophilia (median 4 months, range 1-9).…”

Section: Patients´ Characteristicsmentioning

confidence: 99%

“…If it occurs, resistance is usually associated with point mutations in the kinase domains of PDGFRA (T674I, D842V) 9,10 or PDGFRB (D850E). 11 Here, we report on 22 patients with myeloid/lymphoid neoplasms with eosinophilia and diverse PDGFRB fusion genes focussing on the heterogeneous clinical, cytogenetic and molecular characteristics at diagnosis. Moreover detailed descriptions of treatment with imatinib in regards to dosing, response and long-term remissions are given.…”

Section: Introductionmentioning

confidence: 99%

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Imatinib in myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRB in chronic or blast phase

et al. 2017

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We evaluated clinical characteristics and outcome on imatinib of 22 patients with myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRB. Median age was 49 years (range 20-80), 91% were male. Fifteen different PDGFRB fusion genes were identified. Eosinophilia was absent in 4/19 (21%) cases and only 11/19 (58%) cases had eosinophils ≥1.5×10/L. On imatinib, 17/17 (100%) patients in chronic phase achieved complete hematologic remission after median 2 months (range 0-13). Complete cytogenetic remission and/or complete molecular remission by RT-PCR were achieved in 12/13 (92%) and 12/14 patients (86%) after median 10 (range 3-34) and 19 months (range 7-110), respectively. In patients with blast phase (myeloid, n = 2; lymphoid, n = 3), treatment included combinations of imatinib (n = 5), intensive chemotherapy (n = 3), and/or allogeneic stem cell transplantation (n = 3). All 3 transplanted patients (complex karyotype, n = 2) experienced early relapse. Initially, patients were treated with imatinib 400 mg/day (n = 15) or 100 mg/day (n = 7), the dose was reduced from 400 mg/day to 100 mg/day during follow-up in 9 patients. After a median treatment of 71 months (range 1-135), the 5-year survival rate was 83%; 4/22 (18%) patients died (chronic phase; n = 2; blast phase, n = 2) due to progression (n = 3) or comorbidity while in remission (n = 1). Of note, 3/4 patients had a complex karyotype. In summary, the most important characteristics of myeloid/lymphoid neoplasms with rearrangement of PDGFRB include (a) male predominance, (b) frequent lack of hypereosinophilia,

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Section: Discussionmentioning

confidence: 92%

Section: Patients´ Characteristicsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Imatinib in myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRB in chronic or blast phase

et al. 2017

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“…SPTPRS is known to develop adaptive resistance to MEK/ERK inhibitors through SRC activation [ 77 ]. Novel fusion genes NDEL1-PDGFRB and PTPRZ1–MET have been recently reported to associate with chemoresistance resistance [ 78 , 79 ]. Epigenetic loss of CDH1 correlates with doxorubicin-induced multidrug resistance in human hepatocellular carcinoma cells [ 80 ].…”

Section: Resultsmentioning

confidence: 99%

Chemopreventive Property of Sencha Tea Extracts towards Sensitive and Multidrug-Resistant Leukemia and Multiple Myeloma Cells

Saeed

Hegazy

et al. 2020

Biomolecules

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The popular beverage green tea possesses chemopreventive activity against various types of tumors. However, the effects of its chemopreventive effect on hematological malignancies have not been defined. In the present study, we evaluated antitumor efficacies of a specific green tea, sencha tea, on sensitive and multidrug-resistant leukemia and a panel of nine multiple myelomas (MM) cell lines. We found that sencha extracts induced cytotoxicity in leukemic cells and MM cells to different extents, yet its effect on normal cells was limited. Furthermore, sencha extracts caused G2/M and G0/G1 phase arrest during cell cycle progression in CCRF/CEM and KMS-12-BM cells, respectively. Specifically, sencha-MeOH/H2O extracts induced apoptosis, ROS, and MMP collapse on both CCRF/CEM and KMS-12-BM cells. The analysis with microarray and COMPARE in 53 cell lines of the NCI panel revealed diverse functional groups, including cell morphology, cellular growth and proliferation, cell cycle, cell death, and survival, which were closely associated with anti-tumor effects of sencha tea. It is important to note that PI3K/Akt and NF-κB pathways were the top two dominant networks by ingenuity pathway analysis. We demonstrate here the multifactorial modes of action of sencha tea leading to chemopreventive effects of sencha tea against cancer.

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“…Recently, a CCDC88C-FLT3 fusion responsive to sorafenib was described in a pediatric patient with clinical features of JMML and monosomy 7 [ 51 ]. Other fusions detected in children with myeloproliferative disease include ALK [ 52 , 53 ], ROS1 [ 52 , 53 ], FIP1L1-RARA [ 54 ], HCMOGT-1-PDGFRB [ 55 ], NDEL1-PDGFRB [ 56 ], and NUP98-HOXA11 [ 57 ]. Although kinase fusion-positive cases without Ras pathway mutation may fulfill the clinical and diagnostic criteria of JMML, they likely represent a genetically distinct myeloproliferative neoplasm in childhood.…”

Section: The Origin Of Jmml: the Ras Pathwaymentioning

confidence: 99%

Current Treatment of Juvenile Myelomonocytic Leukemia

Mayerhofer

Niemeyer

Flotho

2021

JCM

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Juvenile myelomonocytic leukemia (JMML) is a rare pediatric leukemia characterized by mutations in five canonical RAS pathway genes. The diagnosis is made by typical clinical and hematological findings associated with a compatible mutation. Although this is sufficient for clinical decision-making in most JMML cases, more in-depth analysis can include DNA methylation class and panel sequencing analysis for secondary mutations. NRAS-initiated JMML is heterogeneous and adequate management ranges from watchful waiting to allogeneic hematopoietic stem cell transplantation (HSCT). Upfront azacitidine in KRAS patients can achieve long-term remissions without HSCT; if HSCT is required, a less toxic preparative regimen is recommended. Germline CBL patients often experience spontaneous resolution of the leukemia or exhibit stable mixed chimerism after HSCT. JMML driven by PTPN11 or NF1 is often rapidly progressive, requires swift HSCT and may benefit from pretransplant therapy with azacitidine. Because graft-versus-leukemia alloimmunity is central to cure high risk patients, the immunosuppressive regimen should be discontinued early after HSCT.

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NDEL1-PDGFRB fusion gene in a myeloid malignancy with eosinophilia associated with resistance to tyrosine kinase inhibitors

Cited by 10 publications

References 18 publications

Imatinib in myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRB in chronic or blast phase

Imatinib in myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRB in chronic or blast phase

Chemopreventive Property of Sencha Tea Extracts towards Sensitive and Multidrug-Resistant Leukemia and Multiple Myeloma Cells

Current Treatment of Juvenile Myelomonocytic Leukemia

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