Correspondence
Somatic Mutations of IDH1 and IDH2 in the Leukemic Transformation of Myeloproliferative Neoplasms
N Engl J Med 2010; 362:369-370January 28, 2010
- Article
To the Editor:
Somatic mutations affecting the R132 residue of isocitrate dehydrogenase 1 (IDH1) and the homologous IDH2 R172 occur in central nervous system tumors.1,2 Recently (in the Sept. 10 issue of the Journal 3), alterations of IDH1 R132 (in exon 2) were reported in 16 of 188 patients with de novo acute myeloid leukemia, with a strong association with a normal karyotype; however, mutations of IDH2 R172 (in exon 4) were not detected. We sequenced exon 2 of the IDH1 gene and exon 4 of the IDH2 gene in patients with leukemia that had evolved from a myeloproliferative neoplasm harboring a mutation in the Janus kinase 2 (JAK2) gene. Somatic mutations in IDH1 or IDH2 were present in 5 of 16 patients (31%) (Table 1Table 1
IDH Mutations at the Leukemic Transformation of a Myeloproliferative Neoplasm with a JAK2 Mutation in Five Patients.), but these mutations were not present in 180 unselected patients with chronic-phase polycythemia vera or essential thrombocythemia. Among the five patients with IDH mutations, three harbored an IDH1 R132C substitution and two harbored a novel IDH2 R140Q mutation affecting a residue conserved in mouse, yeast, and plant homologues.In Patient 2, an IDH2 R140Q mutation was detected in erythroid colonies with a JAK2 mutation as well as in leukemic blasts (Figure 1AFigure 1
Mutations in IDH1 and IDH2 in Patients with Leukemia Evolving from a Myeloproliferative Neoplasm Harboring a Mutation in JAK2.), indicating that this alteration was acquired early during the progression to leukemia and is not responsible for the block in cellular differentiation that occurs in acute leukemia. Leukemic cells arising from myeloproliferative neoplasms with a JAK2 mutation are commonly JAK2 wild-type,4 although the mechanism by which they become wild-type is unknown. Among the five samples of leukemia cells carrying an IDH mutation, three samples lacked the JAK2 mutation. In two of these three samples, an IDH mutation was present in leukemic blasts with wild-type JAK2 but absent from progenitor colonies with a JAK2 mutation (Figure 1B), establishing the presence of two separate clonal expansions in each patient. In these cases, the separate JAK2-mutant and IDH-mutant clones may represent the shared progeny of an ancestral abnormal clone or the coexistence of two distinct disorders with independent origins.5 Anthony Green, F.R.C.Path., F.Med.Sci.
Philip Beer, F.R.C.Path., Ph.D.
University of Cambridge, Cambridge, United Kingdom
arg1000@cam.ac. uk Financial and other disclosures provided by the authors are available with the full text of this letter at NEJM.org.
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