Editor's ChoiceAcute Myeloid Leukemia

New Target for Anti-Leukemia Attack

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Science Translational Medicine  14 Oct 2009:
Vol. 1, Issue 2, pp. 2ec6
DOI: 10.1126/scitranslmed.3000368

Patients diagnosed with acute myeloid leukemia (AML)—in which the rapid proliferation of abnormal blood cells hinders the production of normal blood cells—face poor odds for long-term survival, even with intensive chemotherapy. Despite advances in treatment options, the American Cancer Society estimates that this disease will cause about 9000 deaths in the United States in 2009. Thus, the identification of crucial therapeutic targets in AML—and new drugs that act on those targets—would be a welcome advance. Now, Hahn et al. have discovered that the tyrosine kinase Syk represents one such target. Previous work revealed that inhibitors of the epidermal growth factor receptor such as gefitinib (Iressa) and erlotinib (Tarceva) cause AML cell differentiation and reduce AML cell viability, even though AML cells do not express this receptor. Furthermore, clinical use of erlotinib for a different cancer led to complete remission of AML in two patients. In the new work, the researchers used complementary approaches to identify the targets of these inhibitors in AML. A proteomics study revealed that gefitinib treatment leads to strong dephosphorylation of Syk, whereas an RNA interference screen showed that SYK inhibition causes AML cell differentiation, as monitored by a complex gene expression signature. Syk also appears to be expressed and constitutively active in samples from patients with AML. Additionally, the Syk inhibitor R406, which is already being tested in clinical trials for other purposes, reduces Syk phosphorylation, induces AML cell differentiation, and decreases the leukemia burden in mouse models of AML, indicating that clinical trials of Syk inhibitors are warranted for AML.

C. K. Hahn et al., Proteomic and genetic approaches identify Syk as an AML target. Cancer Cell16, 281–294 (2009). http://www.cell.com/cancer-cell/abstract/S1535-6108(09)00291-8

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