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Is JAK2 Moving Toward Prime Time in Essential (Primary) Thrombocythemia?
Editorial Is JAK2 Moving Toward Prime Time in Essential (Primary) Thrombocythemia? Tariq I. Mughal, MD Division of Hematology and Stem Cell Transplantation University of Texas Southwestern School of Medicine, Dallas
After the initial descriptions of polycythemia vera by Louis Vasquez (1892) and William Osler (1903) and essential thrombocythemia (ET) by Epstein and Goedel (1934), there was no real progress until 1951, when William Dameshek proposed that such diseases and idiopathic myelofibrosis, chronic myeloid leukemia, and erythroleukemia should be grouped together in the general category of myeloproliferative syndromes. This attracted much debate, and many hematologists did not accept this grouping until the remarkable finding in 2005 by several investigators describing the presence of a single acquired point mutation (V617F) in the Janus kinase 2 (JAK2) gene in most patients with polycythemia vera and some with myelofibrosis and ET. The landmarks in the study of chronic myeloid leukemia are, of course, well described and are the single molecular pathogenetic lesion, the Bcr-Abl, and the resultant research that led to the first successful application of molecularly targeted therapy in cancer medicine in 1999. It will be of interest to determine if such success could be reproduced in targeting the JAK2 V617F mutation. Many efforts are being directed toward a better understanding of the molecular biology and, based on the notion that JAK2 inhibitors reduce the growth of JAK2-positive cell lines, many efforts are being directed to develop such agents. The presence of the JAK2 mutation is already having an impact on current treatment algorithms for myeloproliferative disorders. Patients with JAK2-positive ET
appear to have a distinct biologic course and a marked resemblance to polycythemia vera. The precise influence of the mutation on the survival, risk for thrombosis or, indeed, transformation to leukemia is unclear at present. Patients with JAK2-positive ET are more sensitive to hydroxyurea but not anagrelide, which seems not to be influenced by the mutational status. With the increasing availability of accurate diagnostic tests for the JAK2 V617F mutation, revised diagnostic criteria for myeloproliferative disorders have been proposed. A more recent observation has been the presence of a myeloproliferative leukemia mutation in a minority of patients with myeloproliferative disorders. In this issue of Clinical Leukemia, Marson and Harrison present a timely comprehensive review highlighting the current scenario and some controversies pertaining to ET in general. They also address current management issues, particularly those highlighted by a United Kingdom Medical Research Council Primary Thrombocythemia 1 study that included patients at high risk for vascular complications, randomized to receive anagrelide/low-dose acetylsalicylic acid or hydroxyuria/ low-dose acetylsalicylic acid. Although much work lies ahead, it seems likely that the management of patients with myeloproliferative disorders should improve substantially in the foreseeable future. Tariq I. Mughal, MD Associate Editor-in-Chief
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1931-6925, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
Clinical Leukemia • March 2007
143
After the initial descriptions of polycythemia vera by Louis Vasquez (1892) and William Osler (1903) and essential thrombocythemia (ET) by Epstein and Goedel (1934), there was no real progress until 1951, when William Dameshek proposed that such diseases and idiopathic myelofibrosis, chronic myeloid leukemia, and erythroleukemia should be grouped together in the general category of myeloproliferative syndromes. This attracted much debate, and many hematologists did not accept this grouping until the remarkable finding in 2005 by several investigators describing the presence of a single acquired point mutation (V617F) in the Janus kinase 2 (JAK2) gene in most patients with polycythemia vera and some with myelofibrosis and ET. The landmarks in the study of chronic myeloid leukemia are, of course, well described and are the single molecular pathogenetic lesion, the Bcr-Abl, and the resultant research that led to the first successful application of molecularly targeted therapy in cancer medicine in 1999. It will be of interest to determine if such success could be reproduced in targeting the JAK2 V617F mutation. Many efforts are being directed toward a better understanding of the molecular biology and, based on the notion that JAK2 inhibitors reduce the growth of JAK2-positive cell lines, many efforts are being directed to develop such agents. The presence of the JAK2 mutation is already having an impact on current treatment algorithms for myeloproliferative disorders. Patients with JAK2-positive ET
appear to have a distinct biologic course and a marked resemblance to polycythemia vera. The precise influence of the mutation on the survival, risk for thrombosis or, indeed, transformation to leukemia is unclear at present. Patients with JAK2-positive ET are more sensitive to hydroxyurea but not anagrelide, which seems not to be influenced by the mutational status. With the increasing availability of accurate diagnostic tests for the JAK2 V617F mutation, revised diagnostic criteria for myeloproliferative disorders have been proposed. A more recent observation has been the presence of a myeloproliferative leukemia mutation in a minority of patients with myeloproliferative disorders. In this issue of Clinical Leukemia, Marson and Harrison present a timely comprehensive review highlighting the current scenario and some controversies pertaining to ET in general. They also address current management issues, particularly those highlighted by a United Kingdom Medical Research Council Primary Thrombocythemia 1 study that included patients at high risk for vascular complications, randomized to receive anagrelide/low-dose acetylsalicylic acid or hydroxyuria/ low-dose acetylsalicylic acid. Although much work lies ahead, it seems likely that the management of patients with myeloproliferative disorders should improve substantially in the foreseeable future. Tariq I. Mughal, MD Associate Editor-in-Chief
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1931-6925, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
Clinical Leukemia • March 2007
143