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Pellegrino Musto,1 Vittorio Simeon,2 Roberto Guariglia,3 Gabriella Bianchino,4 Vitina Grieco,4 Filomena Nozza,4 Francesco La Rocca,2 Gioacchino Marziano,1 Anna Vittoria Lalinga,5 Emiliano Fabiani,6 Maria Teresa Voso,6 Patrizia Scaravaglio,7 Cristina Mecucci,8 Giovanni D'Arena31Scientific Direction, 2Laboratory of Preclinical and Translational Research, 3Unit of Hematology and Stem Cell Transplantation, 4Laboratory of Clinical Research and Advanced Diagnostics, 5Pathology Unit, IRCCS, Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture, Italy; 6Department of Hematology, Universita Cattolica del Sacro Cuore, Rome, Italy; 7Laboratory of Internal Medicine and Hematology, S Luigi Gonzaga Hospital, Orbassano, Italy; 8Hematology and Bone Marrow Transplantation Unit, University of Perugia, Perugia, ItalyAbstract: The concomitant presence of del(5q) and JAK2V617F mutation is an infrequent event which occurs in rare patients with peculiar cytogenetic, molecular, morphological and clinical features, resembling those of both myelodysplastic syndromes and myeloproliferative neoplasms. Lenalidomide may induce rapid, profound, and long-lasting responses in a subset of these patients. However, the mechanism(s) by which the drug acts in these conditions remain not completely elucidated. A new case report and a review of all cases published so far in this setting are provided. Furthermore, the possibility of categorizing – from a clinical, pathological, and biological point of view – for at least some of these patients as a potential distinct entity is discussed.Keywords: myelodysplastic syndromes, myeloproliferative neoplasms, lenalidomide, del(5q), JAK2, World Health Organization

Protein tyrosine kinases play a crucial role in normal and neoplastic cell development. Recently, a unique clonal mutation in the JAK2 gene that results in a valine to phenylalanine substitution at position 617 (V617F), leading to constitutive JAK2 activation and abnormal signaling, was found in the majority of BCR-ABL negative chronic myeloproliferative disorders (CMPD) patients. Although JAK2 activation by tyrosine phosphorilation is involved in the BCR-ABL transformation of CML cells, V617F mutation is not usually observed in Ph-positive leukemias.We describe two patients with BCR/ABL+ (p190) CML which followed a Ph- CMPD characterized by JAK2 mutation. Patient 1 was diagnosed as having a idiopathic myelofibrosis in Oct 1997. At that time a Ph-chromosome was not detected. The patient remained untreated until March 1999, when WBC started to increase up to 90.000/cmm with a parallel drop in platelet count and increase in spleen size. Hydroxiurea was started with partial hematological remission. In Jan 2000 the presence of a BCR/ABL transcript (p190 type) and a Ph-chromosome in 84% of the cells were observed. Imatinib treatment resulted in a initial improvement, soon followed by progressive increase in the WBC and platelet counts, in spite of a reduction of Ph+ cells to 4%. Hydroxyurea was added but hematological control remained unsatisfactory and imatinib treatment was stopped after 6 months. The patient continued on hydroxyurea for the following year. In 2002 he developed a myeloid blast crisis; karyotype was normal, 4.8% of the cells were Ph+ at FISH and the p190 transcript was still present at low levels. Patient 2 was diagnosed as essential throbocythemia in 1990; cytogenetic analysis showed a normal karyotype. A good control of the thrombocytosis was obtained with hydroxyurea for more than 10 years. In 2003 the hematological data showed leukocytosis (up to WBC 42.900/cmm), immature myeloid cells and 16% monocytes in PB. A masked Ph chromosome was observed by FISH in 47% of cells. RT-PCR was positive for a p190 transcript. The patient started therapy with imatinib which induced a rapid decrease in WBC count; however, the platelet count rised up to 977.000/cmm and hydroxiurea was added again. In subsequent bone marrow samples a progressive decrease of BCR/ABL positive cells to 2% was observed and a BCR-ABL/ABL ratio of 0.18 % was reached in January 2006. However, continuous hydroxyurea therapy was needed to partially control thrombocytosis. Both patients were tested for the presence of JAK2 mutation using the ABI Prims 3100 genetic analyzer and a JAK2-V617F mutation was present. Presence of two clones, possibly derived from a common abnormal stem cell, can be hypothesized in these cases. The possibility of a multistep patogenesis for CML has been widely discussed; in these patients, CML apparently developed as a late event, partially replacing a Ph-CMPD cell population characterized by the JAK2 mutation. Imatinib treatment allowed the reexpansion of the Ph- cells resulting in a overall poor hematological control. Both patients only displayed p190 BCR/ABL transcript, a quite unusual finding in chronic phase CML. It is not clear if any relationship may sussist between this molecular event and the unusual clinical history of these patients.

Pellegrino Musto,1 Vittorio Simeon,2 Roberto Guariglia,3 Gabriella Bianchino,4 Vitina Grieco,4 Filomena Nozza,4 Francesco La Rocca,2 Gioacchino Marziano,1 Anna Vittoria Lalinga,5 Emiliano Fabiani,6 Maria Teresa Voso,6 Patrizia Scaravaglio,7 Cristina Mecucci,8 Giovanni D'Arena31Scientific Direction, 2Laboratory of Preclinical and Translational Research, 3Unit of Hematology and Stem Cell Transplantation, 4Laboratory of Clinical Research and Advanced Diagnostics, 5Pathology Unit, IRCCS, Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture, Italy; 6Department of Hematology, Universita Cattolica del Sacro Cuore, Rome, Italy; 7Laboratory of Internal Medicine and Hematology, S Luigi Gonzaga Hospital, Orbassano, Italy; 8Hematology and Bone Marrow Transplantation Unit, University of Perugia, Perugia, ItalyAbstract: The concomitant presence of del(5q) and JAK2V617F mutation is an infrequent event which occurs in rare patients with peculiar cytogenetic, molecular, morphological and clinical features, resembling those of both myelodysplastic syndromes and myeloproliferative neoplasms. Lenalidomide may induce rapid, profound, and long-lasting responses in a subset of these patients. However, the mechanism(s) by which the drug acts in these conditions remain not completely elucidated. A new case report and a review of all cases published so far in this setting are provided. Furthermore, the possibility of categorizing – from a clinical, pathological, and biological point of view – for at least some of these patients as a potential distinct entity is discussed.Keywords: myelodysplastic syndromes, myeloproliferative neoplasms, lenalidomide, del(5q), JAK2, World Health Organization