<scp>FGFR</scp>1 and <scp>KAT6A</scp> rearrangements in patients with hematological malignancies and chromosome 8p11 abnormalities: biological and clinical features
Authors: Carmen Baldazzi, Simona Luatti, Stefania Paolini, Cristina Papayannidis, Giulia Marzocchi, Gaia Ameli, Giovanni Martinelli, Michele Cavo, Nicoletta Testoni
Journal: American Journal of Hematology (2015)

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 T-lymphoblastic 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′ and 3′ 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 1. 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′ 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 was made. This is a rare clinical presentation among patients with KAT6A rearrangements and it has been reported only in another case showing KAT6A amplification 4. FGFR1 rearrangements were detected in four cases and were associated with four different translocations: t(8;13)(p11;q12), t(8;9)(p11;q33), t(6;8)(q27;p11) and t(8;22)(p11;q11). Three patients showed classical rearrangement, while the patient with t(8;13), showed a deletion 5′ of FGFR1 on the der(8), that has been frequently reported in cases with t(8;13) (Supporting Information, Fig. S2C,D). Patients with FGFR1 rearrangements were characterized by heterogeneous clinical features. Translocation t(6;8) occurred in a patient with a previous history of JAK2 wild-type polycythemia vera (PV). Karyotype was not performed at diagnosis and 2 years later, she developed a T-LBL with multiple lymph nodes involvement. At the same time, BM biopsy revealed a myelodysplastic/myeloproliferative syndrome and cytogenetic analysis showed the presence of t(6;8). PV has been frequently reported in EMS patients with t(6;8) 1. The case with t(8;22) has been previously reported by our group. She presented with B-cell acute lymphoblastic leukemia (B-ALL) and complex karyotype with abnormalities targeting genes involved in lymphoid development 5. A diagnosis of chronic myelomonocytic leukemia (CMML) with eosinophilia but without lymph nodes involvement was made in the patient with t(8;9). CMML has been associated with t(8;9) and a typical site of T-LBL localization has been reported to be the tonsils 1; however, our patient underwent tonsillectomy when he was 15 years old, and this could explain the absence of lymphoid involvement. The case with t(8;13) presented with T lymphoblastic lymphoma with multiple lymphoadenopathies, blood count showed marked leukocytosis with myeloid precursors and BM biopsy was suggestive of unclassified myeloproliferative neoplasm (MPN-U). Among the patients showing neither FGFR1 nor KAT6A rearrangements, a novel translocation t(8;20)(p11;p13) was identified in a patient showing the involvement of both lymphoid and myeloid lineages suggesting that the translocation occurred in an early hematopoietic progenitor as hypothesized for EMS. However, FISH analysis failed to identify FGFR1 rearrangement and showed a deletion encompassing the FGFR1 on der(8) that was found in another case with dic(8;12) and diagnosis of sarcoma with lymph nodes localization (Supporting Information, Fig. S2E,F). Deletion of FGFR1 gene and its surrounding regions has not been previously reported and can suggest the presence of tumor suppressor genes close to FGFR1 with important role in disease pathogenesis. Our data supported the association between some clinical features and specific fusion genes and their role in influencing the disease phenotype. However, heterogeneity can also be found among cases with the same partner gene, suggesting that other mechanisms, like the stage of differentiation of the pluripotent stem cell in which the rearrangement occurred, or the presence of additional abnormalities, could be responsible for the clinical variability of EMS. Both FGFR1 and KAT6A rearrangements are associated with resistance to chemotherapy and poor outcome. Only three patients (two with FGFR1 and one with KAT6A rearrangement), who underwent allogeneic stem cell transplant (alloSCT) alloSCT, were alive and in complete remission 6, 15 and 8 years after the initial diagnosis (Table 1). Finally, our data showed that characteristics related to EMS are not always present in case with FGFR1 rearrangements and, on the other hand, the presence of 8p11 abnormalities and clinical features of EMS not necessarily indicate FGFR1 involvement. Therefore, FISH analysis to assess FGFR1 involvement is mandatory in cases with 8p11 abnormalities to identify high-risk patients that could benefit from future target therapy with new TKI inhibitors. Indeed, ponatinib has recently showed a strong suppressor activity against cell harboring or transfected with different FGFR1 fusion genes 6. Since the poor prognosis associated with KAT6A rearrangement, we also suggest to perform FISH analysis to investigate KAT6A gene in hematological malignancies with 8p11 abnormalities without FGFR1 rearrangements, at least in AML without complex karyotype. To date, alloSCT is the only therapeutic choice to obtain long-term survival and should be considered early in patients with FGFR1 and KAT6A rearrangements. CB designed the study and prepared the manuscript; SL, GM and GA performed conventional cytogenetic analysis and FISH; SP and CP collected clinical data; MC and GM were involved in revising the manuscript; NT gave final approval for submission. Michele Cavo has received honoraria and has been a member of the advisory board for Celgene, Jansen-Cilagand Novartis. Giovanni Martinelli is a consultant of Novartis, Pfizer and Ariad and is a member of the speakers bureau of Novartis. All other authors declare to have no financial interest in competing. This study was supported by University of Bologna (RFO), Associazione Italiana contro le Leucemie, linfomi e mieloma multiplo (BolognAIL) and European LeukemiaNET. Carmen Baldazzi,* Simona Luatti, Stefania Paolini, Cristina Papayannidis,Giulia Marzocchi, Gaia Ameli, Giovanni Martinelli Michele Cavo and Nicoletta Testoni Institute of Hematology and Medical Oncology, "Lorenzo E Ariosto Seràgnoli", Sant'Orsola-Malpighi Hospital-University of Bologna, Bologna, Italy