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Myeloid/lymphoid neoplasms with eosinophilia (MLNe) associated with PDGFRA rearrangement are rare disorders. The most frequent PDGFRA abnormalities is FIP1L1/PDGFRA (F/P) fusion gene results from a cryptic interstitial deletion at 4q12 with constitutive activation of tyrosine kinase (TK) activity. Although known since 2003, many questions remain in understanding the biology, disease course and response to therapy. The F/P fusion gene may clinically present as chronic eosinophilic leukemia (CEL), T-cell lymphoblastic lymphoma (T-LBL) or both concurrently. Acute myeloid leukaemia (AML) may also occur at presentation or during the course of the disease. While F/P is the driver mutation, to date there are few data about genetic variants of the disease that may contribute to clinical outcome. CCAAT/enhancer binding protein alpha (CEBPA) gene functions as key regulator of granulocytic differentiation. CEBPA mutations contribute to leukemogenesis by promoting proliferation and blocking differentiation of myeloid lineage in AML. Germline CEBPA mutations is a very rare and account about 1% in AML only.

A 26 year-old male patient was presented with a 4-week history of fever, fatigue, difficulty in swallowing. Physical examination revealed generalized lymphadenopathy, splenomegaly, tonsils enlargement, leukocytosis (20x10⁹/L), with marked eosinophilia (4,0x10⁹/L). A bone marrow aspirate showed 2% blasts, 21% eosinophils. Histological examination of an cubital lymph node biopsy showed diffuse proliferation of medium-sized lymphoblasts. Immunohistochemistry and flow cytometry showed that the lymphoblastic population expressed CD2, CD5, CD7, CD4, CD99, TdT and CD1a. Polymerase chain reaction (PCR) analysis from samples of the lymph node and bone marrow failed to detect clonal T-cell receptor rearrangement. A diagnosis of T-cell lymphoblastic lymphoma (T-LBL) associated with reactive eosinophilia was rendered. The patient began standard multiagent chemotherapy in accordance with ALL-2009 protocol (ClinicalTrials.gov Identifier: NCTO1193933) and achieved complete clinical remission. As he was planned to conduct autologous hematopoietic stem cell transplantation (HSCT), blood hematopoietic stem cells have been successfully harvested after stimulation of hematopoiesis. However, within 10 days after the discontinuation of G-CSF he developed leukocytosis (130x10⁹/L) with 21% of eosinophils (absolute number 27,3x10⁹/L) and cubital lymphadenopathy. Histological examination of lymph node showed T-LBL relapse. Bone marrow biopsy revealed the expansion of predominantly eosinophilic cells. The study was carried out to exclude second myeloproliferative disease. Molecular and cytogenetic examinations of bone marrow failed to reveal BCR-ABL, FLT3 and NPM1, but showed CEBPA (TAD2) mutation. FISH probe revealed deletion 4q12 (F/P rearrangement), confirmed by RT-PCR. The same changes were also found in the lymph node cells. So, in accordance with 2008 WHO classification, he was diagnosed as «PDGFRA-associated MLNe». The patient was subsequently treated with imatinib mesylate at the dose 100mg daily and showed a good clinical response. After 4 months minimal residual disease still persisted in bone marrow (RT-PCR positive for F/P and PCR for CEBPA mutation) and he received an allogeneic HSCT from his brother. Routine testing of chimerism at 2 months after HSCT revealed the recipient DNA less than 5% and positive probe for F/P and CEBPA. We hypothesized the germinal origin of CEBPA mutation.

Germline CEBPA mutations is very rare event and have been identified as causative gene mutations in familial AML. For the first time to our knowledge this mutation was detected in patient with PDGFRA-associated MLNe. This observation is of particular interest because it will provide novel insight about the genetic basis and the additional events responsible for the course of the disease.