Identification and functional characterization of imatinib‐sensitive DTD1‐PDGFRB and CCDC88C‐PDGFRB fusion genes in eosinophilia‐associated myeloid/lymphoid neoplasms

Eosinophilia‐associated myeloid neoplasms with rearrangement of chromosome bands 5q31‐33 are frequently associated with PDGFRB fusion genes, which are exquisitely sensitive to treatment with imatinib. In search for novel fusion partners of PDGFRB, we analyzed three cases with translocation t(5;20)(q33;p11), t(5;14)(q33;q32), and t(5;17;14)(q33;q11;q32) by 5′‐rapid amplification of cDNA ends polymerase chain reaction (5′‐RACE‐PCR) and DNA‐based long‐distance inverse PCR (LDI‐PCR) with primers derived from PDGFRB. LDI‐PCR revealed a fusion between CCDC88C exon 25 and PDGFRB exon 11 in the case with t(5;17;14)(q33;q11;q32) while 5′‐RACE‐PCR identified fusions between CCDC88C exon 10 and PDGFRB exon 12 and between DTD1 exon 4 and PDGFRB exon 12 in the cases with t(5;14)(q33;q32) and t(5;20)(q33;p11), respectively. The PDGFRB tyrosine‐kinase domain is predicted to be retained in all three fusion proteins. The partner proteins contained coiled‐coil domains or other domains, which putatively lead to constitutive activation of the PDGFRB fusion protein. In vitro functional analyses confirmed transforming activity and imatinib‐sensitivity of the fusion proteins. All three patients achieved rapid and durable complete hematologic remissions on imatinib. © 2014 Wiley Periodicals, Inc.     

Identification of a MYO18A‐PDGFRB fusion gene in an eosinophilia‐associated atypical myeloproliferative neoplasm with a t(5;17)(q33‐34;q11.2)

Chromosomal aberrations of 5q31‐33 associated with rearrangements of the platelet‐derived growth factor receptor beta (PDGFRB) gene are rare but recurrent in patients with eosinophilia‐associated atypical myeloproliferative neoplasms (Eos‐MPNs). We used a DNA‐based “long‐distance inverse PCR” (LDI‐PCR) to identify a new MYO18A‐PDGFRB fusion gene in an Eos‐MPN with associated t(5;17)(q33‐34;q11.2). MYO18A is the fourth partner gene after BCR, ETV6 and SPTBN1 that fuses to more than one tyrosine kinase gene. Treatment with imatinib (400 mg/day) led to rapid and sustained complete hematologic, cytogenetic and molecular remission. Patients with PDGFRB fusions genes are excellent candidates for treatment with imatinib; complete cytogenetic and even molecular remissions are common while primary or secondary resistance seems to be very rare. © 2008 Wiley‐Liss, Inc.     

SFPQ‐ABL1‐positive B‐cell precursor acute lymphoblastic leukemias

In recent years, a subgroup of B‐cell precursor acute lymphoblastic leukemia (BCP ALL) without an established abnormality (“B‐other”) has been shown to be characterized by rearrangements of ABL1, ABL2, CSF1R, or PDGFRB (a.k.a. ABL‐class genes). Using FISH with probes for these genes, we screened 55 pediatric and 50 adult B‐other cases. Three (6%) of the adult but none of the childhood B‐other cases were positive for ABL‐class aberrations. RT‐PCR and sequencing confirmed a rare SFPQ‐ABL1 fusion in one adult B‐other case with t(1;9)(p34;q34). Only six SFPQ‐ABL1‐positive BCP ALLs have been reported, present case included. A review of these shows that all harbored fusions between exon 9 of SFPQ and exon 4 of ABL1, that the fusion is typically found in adolescents/younger adults without hyperleukocytosis, and that IKZF1 deletions are recurrent. The few patients not treated with tyrosine kinase inhibitors (TKIs) and/or allogeneic stem cell transplantation relapsed, strengthening the notion that TKI should be added to the therapy of SFPQ‐ABL1‐positive BCP ALL.     

Fusion of PRKG2 and SPTBN1 to the platelet-derived growth factor receptor beta gene (PDGFRB) in imatinib-responsive atypical myeloproliferative disorders

Chromosomal translocations involving the platelet-derived growth factor receptor beta gene (PDGFRB) have been reported in a subset of patients with atypical myeloproliferative disorders (MPDs). The fusion of the PDGFRB gene, which encodes a tyrosine kinase receptor, with different partner genes results in its constitutive activation. We present the cases of two patients with atypical MPD carrying t(4;5)(q21;q33) and t(2;5)(p21;q33), respectively. Fluorescence in situ hybridization demonstrated that PDGFRB was involved in both translocations. Further characterization of the 4q21 breakpoint using a bacterial artificial chromosome probe revealed PRKG2 as the likely gene partner to PDGFRB. Characterization of the 2p21 breakpoint identified a novel gene partner to PDGFRB, the SPTBN1 gene. Both patients achieved a complete molecular remission after introduction of imatinib mesylate therapy.     

Simultaneous occurrence of t(9;22)(q34;q11.2) and t(16;16)(p13;q22) in a patient with chronic myeloid leukemia in blastic phase

Coexistence of two specific chromosomal translocations in the same clone is an infrequent phenomenon and has only rarely been reported in hematological malignancies. We report a combination of t(16;16)(p13;q22), the Philadelphia translocation t(9;22)(q34;q11.2), and deletion of the long arm of chromosome 7 in a patient with chronic myeloid leukemia in blast phase. Monotherapy treatment with imatinib mesylate resulted in the disappearance of the Ph-positive clone, but with persistence of t(16;16) and del(7) in all of the metaphases examined. The case illustrates that, although imatinib mesylate can be an effective treatment in eradication of the BCR–ABL fusion gene cells, the occurrence of additional specific abnormalities in Philadelphia-positive leukemias may pose a significant therapeutic challenge.     

PDGRFB mutation‐associated myofibromatosis: Response to targeted therapy with imatinib

Heterozygous activating mutations in platelet‐derived growth factor receptor B (PDGFRB) have been recently identified as a cause of autosomal‐dominant infantile myofibromatosis. We describe a 36‐year‐old man with PDGFRB c.1681C>T (p.R561C) mutation. Upon progressive disease, the patient received treatment with imatinib and showed a remarkable response with remission of multiple lesions after 12 months. This is the first report of an adult patient with PDGFRB c.1681C>T mutation treated with imatinib.     

逆转录-多重巢式聚合酶链反应技术在急性单核系白血病M4/M5 MLL基因重排检测中的应用

目的 探讨逆转录-多重巢式聚合酶链反应（多重PCR）技术在初诊M4／M5患者MLL基因重排检测中的价值。方法 采用骨髓直接或短期培养法制备染色体，应用R显带技术进行核型分析。采用多重PCR技术，检测40例初诊M4／M5患者中5种急性髓系白血病常见的MLL融合基因以及MLL部分串联重复。结果 R显带揭示7有涉及11q23的易位，包括t（6；11）（q27；q23）、t（9；11）（p21；q23）、t（11；17）（q23；q21）、t（11；19）（q23；p13．1），14例有其他核型异常，19例为正常核型。多重PCR证实了7例核型分析显示11q23易位标本中的6例，例3核型分析揭示46，XX，t（6；11）（q27；q23），多重PCR检测MLL/AF6为阴性；19例显带分析为正常核型标本中检出2例MLL部分串联重复。结论 多重PCR是对初诊M4／M5患者进行各种MLL重排筛检的有效方法。