2009.05.29 – TET2 defects present early in myeloid cancers


Posted May 29, 2009

TET2 defects present early in myeloid cancers

TET2 mutations or deletions may be early events in patients with myelodysplastic syndromes, myeloproliferative disorders or secondary acute myeloid leukemia, according to data from an analysis. In those patients with both TET2 and JAK2 mutations, the researchers found that TET2 mutations occurred first.

“It is now clear that activating mutations of the JAK2 gene occur in most patients with polycythemia vera, essential thrombocythemia or myelofibrosis,” Ross L. Levine, MD, of the Human Oncology and Pathogenesis Program and the Leukemia Service in the Department of Medicine at Memorial Sloan-Kettering Cancer Center, and Martin Carroll, MD, of the Division of Hematology and Oncology at the University of Pennsylvania, wrote in an accompanying editorial.

According to Levine and Carroll, these data suggest that uninhibited JAK2 signaling is a causal event in myeloproliferative disorders.

The researchers conducted molecular, cytogenetic, comparative genomic-hybridization and single-nucleotide-polymorphism analyses to identify a tumor-suppressor gene common in patients with myelodysplastic syndromes, myeloproliferative disorders and AML. The researchers determined the coding sequence of TET2 in 320 patients. Using in vitro clonal assays and transplantation of human tumor cells into mice, they analyzed the consequences of deletions or mutations in TET2.

TET2 mutations or deletions were identified in three patients with myelodysplastic syndromes, three of five patients with myeloproliferative disorders, two with primary AML and one with secondary AML. Six patients with myelodysplastic syndromes or AML carried acquired rearrangements on chromosome 4q24. Five patients with myeloproliferative disorders carried a dominant clone in hematopoietic progenitor cells that was positive for the V617F mutation in the JAK2 gene, according to the researchers.

The researchers found TET2 defects in 19% of patients with myelodysplastic syndromes, 12% of those with myeloproliferative disorders, 24% of those with secondary AML and 22% of those with chronic myelomonocytic leukemia. TET2 defects preceded JAK2 V617F mutation in five samples from patients with myeloproliferative disorders and were present in hematopoietic stem cells.

“The results of the study by Delhommeau et al suggest that effective inhibition of JAK2 may suppress the TET2-JAK2 mutation cell but not the parental TET2 mutant cell,” Levine and Carroll wrote. “If so, patients with myeloproliferative disorders will probably need long-term therapy with JAK2 inhibitors and continued surveillance for cancers arising from JAK2 wild-type clones.”

Delhommeau F. N Engl J Med. 2009;360:2289-2301.