Mark G. Frattini, MD, PhD
In the era of genomic-based approaches and high-throughput sequencing, the most important decision point becomes deciphering which mutations are important in the pathogenesis of the disease in question and which proteins represent possible targets for therapeutic development. With regard to myeloproliferative neoplasms, we are beginning to get some answers.
Yesterday morning, Dr. Ayalew Tefferi from the Mayo Clinic in Rochester, MN, chaired the scientific session titled “Molecular Pathogenesis and Targeted Therapy in Myeloproliferative Neoplasia.” This session detailed the novel set of mutations seen in BCR-ABL negative myeloproliferative neoplasms (MPNs), the use of mouse models to study these diseases, and current clinical trial results using JAK2 inhibitor therapy. The session is repeated today at 9:30 a.m. in Room 330.
Dr. William Vainchenker from the Institut Gustave Roussy in Villejuif, France, detailed a review of the novel mutations seen in this group of diseases (polycythemia vera [PV], essential thrombocythemia [ET], and primary myelofibrosis [PMF]) and their roles in contributing to disease pathogenesis. He outlined that gain-of-function mutations for JAK2 (both JAK2V617F and JAK2exon12) and MPL and loss-of-function mutations for LNK, CBL, and SOCS can lead to the development of the various MPNs. On the other hand, TET2, ASXL1, and EZH2 mutations were found to occur in other myeloid neoplasms in addition to the MPNs, including acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and overlap MDS/MPN. Dr. Vainchenker concluded with a discussion of the TET2 mutation showing that TET mutation resulted in hydroxylation of 5-methylcytosine, resulting in the generation of a previously unknown modified base in mammalian DNA. He also mentioned that the TET2 mutation is found in approximately 14 percent of patients with MPN (higher in PMF) and AML but also in CMML at a much higher percentage (50 percent). He then proposed that TET2 mutation may be present in immature progenitor cells occurring before the JAK2 mutation and showed data from shRNA knockdown experiments in both human and mouse cells that TET2 likely regulates myeloid differentiation.
Dr. Richard Van Etten from Tufts Medical Center in Boston, MA, then focused on both retroviral and transgenic mouse models of the JAK2V617F mutation and described each system in terms of both feasibility and correlation of the results to what happens in the human disease. He showed that in these mice JAK2V617F was necessary and sufficient to induce MPN, the cell of origin likely arises from the hematopoietic stem cell compartment, that gene dosage is important in determining which MPN develops, and finally that the transcription factor STAT5 is required for JAK2-induced MPN. Dr. Van Etten concluded that with use of JAK2 inhibitor therapy in these mouse models both the polycythemia and splenomegaly are reversed but not the myelofibrosis, and JAK2-allele burden was only modestly reduced in published studies.
Dr. Tefferi wrapped up the session with the ATP mimetic JAK2 inhibitors in human clinical trials with PMF. He focused on three inhibitors currently in use in phase I and II clinical trials — INCB018424, TG101348, and CYT387. The results were compared for the effect on spleen-size reduction, resolution of constitutional symptoms, thrombocytopenia, and emergence of anemia as a side effect of therapy. Dr. Tefferi also discussed the known possible off-target effects of these drugs and concluded with a potential treatment algorithm for physicians.
It appears from the early clinical results seen in humans with the various JAK2 inhibitors that all the hard work done in the laboratory has paid off. What has become clear from the recent laboratory work is that there is still much to do.
Dr. Frattini indicated no relevant conflicts of interest.