FGFR1 and KAT6A rearrangements in patients with hematological malignancies and chromosome 8p11 abnormalities: biological and clinical features

Abstract

confirm that mutant PDGFRB is indeed the driver mutation in PDGFRB rearranged myeloid neoplasms, consistent with the robust treatment responses with imatinib, thereby constituting a unique stem cell disorder that should continue to be classified separately. To the Editor: Chromosomal 8p11 abnormalities are rare but recurrent in hematological malignancies and frequently involve the FGFR1 or KAT6A genes. FGFR1 rearrangements are associated with the 8p11 Myeloproliferative Syndrome (EMS), characterized by myeloproliferative neoplasms (MPN) with eosinophilia; lymphadenopathy, usually Tlymphoblastic lymphoma/leukemia (T-LBL); and progression to acute myeloid leukemia (AML) [1]. The 2008 WHO classification of hematopoietic and lymphoid neoplasms classified it as "myeloid and lymphoid neoplasms with FGFR1 abnormalities" in the "myeloid and lymphoid neoplasms associated with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1" category [2]. However, EMS patients, different from patients with PDGFRA and PDGFRB rearrangements, are not sensitive to imatinib therapy. KAT6A rearrangements are associated with aggressive forms of M4-M5 AML, distinctive bone marrow (BM) morphology (e.g. erythrophagocytosis), extramedullary involvement and disseminated intravascular coagulation [3]. In this study, we report the frequency of FGFR1 and KAT6A involvement in patients with 8p11 abnormalities, and the correlation with clinical features.By cytogenetic analysis, we identified 12 patients (0.3%) with chromosome 8p11 abnormalities over 4207 patients diagnosed with myeloid or lymphoid malignancies. A commercially available FGFR1 dual color breakapart probe (Kreatech Diagnostics, The Netherlands) and a KAT6A dual color breakapart probe, designed from bacterial artificial chromosomes (BACs), were used to investigate FGFR1 and KAT6A genes by fluorescence in situ hybridization (FISH). BACs RP11-231D20 and RP11-108L9, mapping 5 0 and 3 0 of KAT6A according to Ensembl (http://www.ensembl.org/), were supplied marked in Spectrum Green and Spectrum Orange, respectively (BlueFISH, Illumina, US) (Supporting Information, Fig. S1).Patients' clinical and cytogenetic characteristics and FISH results are shown in Table I. KAT6A rearrangement was identified in four cases. Two cases had inv(8)(p11q13), one showed t(8;16)(p11;p13) and one had t(8;20)(p11;q13). FISH analysis revealed KAT6A involvement with classical FISH signal pattern in three cases while one patient showed an atypical signal pattern, indicating a deletion 3 0 of KAT6A ( Supporting Information, Fig. S2A,B). Patients with KAT6A rearrangements showed common features such as young age and AMLs with involvement of monocytic lineage. Furthermore, they were associated with extramedullary localization and exposition to previous chemotherapy. No sign of erythrophagocitosis was observed in our cases despite it has been frequently associated with KAT6A rearrangements [3]. In the patient with t(8;16), BM showed 60% of erythroid and 40% of monocytoid blast cells, therefore a diagnosis of AML-M6 ...

Prevalence of chromosome 8p11.2 translocations and correlation with myeloid and lymphoid neoplasms associated with FGFR1 abnormalities in a consecutive cohort from nine institutions in Japan

“…In addition, not all patients with 8p11.2 abnormalities were diagnosed with MLN- FGFR1 abnormalities. About one third of them were categorized as MLN- FGFR1 abnormalities in our study, which was also consistent with a previous report in which four of 14 patients with 8p11.2 translocations and in another report, four of 12 patients with 8p11.2 translocations were diagnosed as MLN- FGFR1 abnormalities [ 5 , 6 ].…”

“…Among them, pemigatinib, a reversible ATP-competitive FGFR inhibitor, has been recently approved as a novel drug for treatment of myeloid/lymphoid neoplasms with FGFR1 rearrangement in the US and Japan. To select appropriate patients for pemigatinib therapy, FISH analysis demonstrating FGFR1 gene disruption would be desirable in addition to chromosomal 8p11.2 abnormalities for patients who do not exhibit the typical clinical features of MLN- FGFR1 abnormalities, because approximately one third of patients with 8p11.2 abnormalities were diagnosed as MLN- FGFR1 abnormalities in our study and previous reports [ 5 , 6 ].…”

Response to Tyrosine Kinase Inhibitors in Myeloproliferative Neoplasia with 8p11 Translocation and CEP110-FGFR1 Rearrangement

“…Table displays a comprehensive overview of published reports, characteristics, treatments, and outcomes of EMS patients. Of 14 previously reported EMS patients, 8 died within 15 months after diagnosis . Six patients underwent allogeneic hematopoietic cell transplantation (HCT), and four of these were long‐term survivors, suggesting this aggressive strategy as the only curative treatment option .…”