Let's not get too JAKed up!

Comment on Goerttler et al, page 2862

Goerttler and colleagues present a classification of the Philadelphia-negative myeloproliferative disorders, based upon a battery of molecular markers.

In this issue, Goerttler and colleagues report their efforts to define a subpopulation of patients with chronic myeloproliferative disorders (cMPDs) based on their use of a battery of molecular markers. The cMPDs, which include polycythemia vera (PV), essential thrombocythemia (ET), and chronic idiopathic myelofibrosis (CIMF) have been historically defined by their clinical characteristics, their unusual ability to evolve into syndromes that possess common features, and their eventual transformation into acute myeloid leukemia. Unlike chronic myeloid leukemia (CML), where an underlying cytogenetic defect and molecular abnormality has been recognized for several decades, a molecular abnormality common to each of the cMPDs has proven elusive. Only in the last year has an acquired somatic mutation affecting the Janus tyrosine kinase 2 (JAK2V617F) been detected in the myeloid cells of a large proportion of patients with PV (80%), ET (50%), and CIMF (50%).^1-4  A variety of other biomarkers have been previously used by numerous investigators to not only discriminate the cMPDs from a variety of reactive processes, but also as a means of stratifying such patients according to their risk for developing either thrombotic complications or acute leukemia.⁵  These biomarkers include the ability of cMPD hematopoietic progenitors to form endogenous erythroid colonies (EECs) in vitro in the absence of erythropoietin, overexpression of polycythemia rubra vera 1 (PRV-1; CD177) mRNA by granulocytes, and the reduced expression of the thrombopoietin receptor c-Mpl, by platelets.

Goerttler and coworkers report in this issue that the JAK2 genotype is closely correlated in patients with PV, ET, and CIMF with the ability of progenitor cells to form EECs and the overexpression of PRV-1 by granulocytes. The other epigenetic marker, platelet c-Mpl expression, varied in this study independent of the ability to form EECs, as well as overexpression of granulocyte PRV-1. As one would anticipate, this study raises as many questions as it answers. Although the clinical manifestations of the cMPDs can vary significantly (PV, ET, CIMF), a uniform subpopulation can apparently be defined based upon molecular characteristics. Will the clinical behavior of these individuals be distinct from that of other subpopulations of patients with cMPDs who do not share such molecular abnormalities? Does the constellation of such markers predict a positive or negative outcome? Can drug therapies alter the expression of such markers of the cMPDs, and will this be associated with a favorable outcome? Each of these questions requires careful studies of large cohorts of patients with cMPDs that are both classified by molecular markers as well as the classical clinical and hematological parameters. Before abandoning our time-tested clinical classification systems of the cMPDs, one should await the completion of studies validating these molecular markers. Such studies will require the cooperation of the medical community at a level that has not been possible in North America for more than 2 decades. In the hoopla surrounding the identification of the JAK2V617F mutation many have presumed that this discovery is equivalent to the identification of the Philadelphia chromosome and its associated Bcr/Abl fusion gene in CML. The CML story, which culminated in the discovery of imatinib, a novel form of targeted chemotherapy, is obviously one of the true victories of molecular medicine. Unfortunately, there is a long road ahead before we can anticipate such a positive outcome in the cMPDs. Since not all patients with cMPDs possess the JAK2V617F mutation, one must be concerned that drugs exclusively targeting this mutation might not be useful for a subpopulation of JAK2V617F-negative patients. This is especially important for CIMF, which is a disorder associated with an especially poor prognosis in its advanced forms and in which only 50% of patients possess the mutation of JAK2. Although new small molecules with activity against JAK2 are currently being discovered with increasing frequency, the ability of such molecules to run the gauntlet of drug development and clinical evaluation prior to approval for the treatment of cMPDs remains a daunting goal. Due to the identification of the JAK2V617F mutation, we are beginning an exciting and productive period of investigation which will likely result in a rapid expansion of our knowledge of the biology and therapy of the cMPDs. This process will require a great deal of hard work and a high degree of scientific rigor, especially in the clinical arena.