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The Lancet Oncology

Monday, January 5, 2009

A Tumor Suppressor Gene Inactivated in Myeloproliferative Neoplasms

Research by Dr. Francois Delhommeau MD, and his team at the Saint-Antoine Hospital, Paris, France (Hôpital Saint Antoine, Service d’hématologie, 184, rue du Faubourg Saint Antoine, 75012 Paris) on treatment advances in leukemia and lymphoma, presented as late-breaking news during the 50th Annual Meeting of the American Society of Hematology in San Francisco, CA,(December 6 – 9, 2008), led to the discovery of a new tumor suppressor gene called TET2 (Ten-Eleven Translocation–2).

Because TET2 is altered in 14 percent of patients with myeloproliferative disorders, the discovery provides scientists with a greater understanding of the underlying biology of these conditions, as well as a potential target for the development of future treatments.

All blood cells start out as hematopoietic, or blood-forming, stem cells and have the potential to become mature red blood cells, white blood cells, or platelets. Myeloproliferative disorders develop when the DNA of a stem cell is altered in the bone marrow, causing the overproduction of some blood cells.

Previous research has detected mutations in other genes– JAK2 and MPL – in the blood stem cells of patients with myeloproliferative disorders. These JAK2 and MPL defects cause the overproduction of mature malignant blood cells, but multiple lines of evidence suggest that these are not the only molecular lesions responsible for abnormalities in the stem cell in these disorders. Greater analysis of blood cell development in myeloproliferative disorders with the JAK2 V617F mutation led researchers to identify two subsets of patients. The first subset of patients (85 percent) had an overproduction of malignant cells mainly dependent on the late stages of blood cell differentiation, far downstream from the stem cell. In contrast, a second subset of patients (15 percent) had an early expansion of very immature malignant progenitor cells, close to the stem cell.

Researchers then hypothesized that the second subset of patients had a pre-existent molecular defect able to promote the early expansion of the malignant cells. With high-resolution arrays, researchers were able to identify one single gene, TET2, which belongs to a family of three genes of unknown function.

Researchers then further analyzed cells in five patients with TET2 mutations, which demonstrated that TET2 defects target hematopoietic stem cells. Moreover, they show that in these five patients TET2 inactivation precedes the JAK2 V617F mutation, suggesting that this new molecular lesion could be an early event in cancer stem cell formation.

To further test these findings, researchers sequenced TET2 in 181 unselected JAK2 V617F patients with myeloproliferative disorders. TET2 mutations were found in 25 of the 181 patients, resulting in an overall 14 percent frequency.

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