A Kinase Mutation Excites the Myeloproliferative Disorders Community

A Kinase Mutation Excites the Myeloproliferative Disorders Community

by David W. Sharp

WHAT'S HOT IN MEDICINE
Rank	Paper	Citations This Period (Jul-Aug 06)	Rank Last Period (May-Jun 06)
1	R.S. Bresalier, et al., "Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial," New Engl. J. Med., 352(11): 1092-1102, 17 March 2005. [8 institutions worldwide] *906PU	58	8
2	S.R. Solomon, et al., "Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention,"New Engl. J. Med., 352(11): 1071-80, 17 March 2005. [5 U.S. and U.K. institutions] *906PU	52	†
3	P.M. Ridker, et al., "C-reactive protein levels and outcomes after statin therapy," New Engl. J. Med., 352(1): 20-8, 6 January 2005. [Brigham & Women’s Hosp., Harvard Med. Sch., Boston, MA] *884UP	50	†
4	W. Pao, et al., "EGF receptor gene mutations are common in lung cancers from ‘never smokers’ and are associated with sensitivity of tumors to gefitinib and erlotinib," Proc. Natl. Acad. Sci. USA, 101(36): 13306-11, 7 September 2004. [Mem. Sloan-Kettering Cancer Ctr., New York, NY; Washington U. Sch. Med., St. Louis, MO] *853AT	48	7
5	R. Kralovics, et al., *"A gain-of-function mutation of JAK2* in myeloproliferative disorders,"** New Engl. J. Med., 352(17): 1779-90, 28 April 2005. [U. Hosp. Basel, Switzerland; U. Pavia Med. Sch., Italy] *920KY	46	†
6	C. James, et al., *"A unique clonal JAK2* mutation leading to constitutive signalling causes polycythaemia vera,"** Nature, 434(7037): 1144-8, 28 April 2005. [7 French and Belgian institutions] *920MD	44	†
7	R. Stupp, et al., "Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma," New Engl. J. Med., 352(10): 987-96, 10 March 2005. [15 European and Canadian institutions] *904JC	43	†
8	F.A. Shepherd, et al., "Erlotinib in previously treated non-small-cell lung cancer," New Engl. J. Med., 353(2): 123-32, 14 July 2005. [15 institutions worldwide] *944OP	40	10
9	T.J. Curiel, et al., "Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival," Nature Medicine, 10(9): 942-9, September 2004. [5 U.S. institutions] *851AZ	39	†
10	O. Abe, et al. (Early Breast Cancer Trialists’ Collaborative Group), "Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials," Lancet, 365(9472): 1687-1717, 14 May 2005. [c. 150 institutions worldwide] *925VV	39	†
SOURCE: Thomson Scientific's Hot Papers Database. Read the Legend.

owards the end of 2005 a group of research workers met in Paris for the first international meeting on the V617F JAK2 mutation in myeloproliferative disorders. In December, 2006, the American Society of Hematology’s annual meeting devoted a session to the topic, including the possibility of small-molecule inhibitors of JAK-STAT and the effect on disease classification and diagnosis of findings that first appeared in general journals (on the current list, papers #5 and #6, along with E. J. Baxter, et al., Lancet, 9464[365]: 1054-61, 2005; currently paper #14, total cites 170, latest count 36). But we had better begin at the beginning. The JAK family ("just another kinase," or a reference to two phosphate-transferring domains and the two-faced Roman god Janus) has four members. JAK2, with signal transducers and activators of transcription, make up the JAK-STAT package of current interest. There are three major myeloproliferative disorders—polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis. All can be blamed on an aberrant hematopoietic stem cell and probably reflect some abnormality in signalling pathways (#14). The V617F mutation causes a single change (valine to phenylalanine) at position 617 in JAK2’s amino-acid sequence.

Dr. Chloé James and her colleagues (#6) were prompted to look for mutations in the gene for JAK2 (JAK2) by their findings on the role of this kinase in the formation of endogenous erythroid colonies and in erythropoietin receptor signalling. As Dr. John Goldman notes in his editorial accompanying paper #5 (J.M. Goldman, New Engl. J. Med., 352[17], 1744-6, 2005), all three research groups (#5, #6, #14) had different reasons for looking into JAK2. So did a Boston-based team whose paper appeared at the same time (R.L. Levine, et al., Cancer Cell, 7[4]: 387-97, 2005). If anything, that strengthens the validity of the multiple confirmation. In these first four sets of data the proportion of polycythemia vera patients who were positive for V617F was 77% but with considerable variation in the four different series.

If this field can be said to have opened up around April, 2005, where does it stand at the end of 2006? Science Watch asked Dr. Jean-Jacques Kiladjian, lead rapporteur for the Paris meeting (J.-J. Kiladjian, et al., J. Path. Biol., doi:10.1016/j.patbio.2006.06.004) whether the diagnosis and classification of myeloproliferative disorders have changed and if new treatments are realistically in prospect as a result of the focus on JAK2.

Dr. Kiladjian is unaware of any specific JAK2 inhibitors currently undergoing clinical trials, but disease management has been changed by the discovery of the mutation. "For the first time we have a tool to monitor minimal residual disease in myeloproliferative disorders," Dr. Kiladjian tells Science Watch. Using this tool, various groups have found that hydroxycarbamide, standard interferon (IFN) alfa, and pegylated (PEG) IFN alfa-2b do not seem to affect clonal proliferation in patients in hematological remission. In contrast, Kiladjian’s group observed a high rate of molecular response (including one complete disappearance of mutant JAK2) in polycythemia vera patients treated with PEG IFN alfa-2a (J.-J. Kiladjian, et al., Blood, 108[6]:2037-40, 2006). "So, we think that PEG IFN alfa-2a should rapidly be compared in a randomized trial with the current reference drug, hydroxycarbamide." If the efficacy of PEG IFN alfa-2a is confirmed, "we could already have a drug with a specific activity against JAK2 V617F that is widely used and has a well-described safety profile." Any future specific JAK2 inhibitors, Kiladjian concludes, would then have to be compared with PEG IFN alfa-2a.

Mr. David W. Sharp, M.A. (Cambridge) is contributing editor,
The Lancet, London, U.K.


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Science Watch^®, January/February 2007, Vol. 18, No. 1
Citing URL: http://www.sciencewatch.com/jan-feb2007/sw_jan-feb2007_page5.htm