Cooperative Pathways to Acute Myeloid Leukemia Include the Combining of Transcription Factor Alterations: PML-RARα Cooperates with SOX4.

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One paradigm for transformation of normal myeloid cells into acute myeloid leukemia (AML) is the combining of transcription factor alteration with activation of signaling pathways, including cytokine receptor activation. To identify possible alternative pathways to leukemogenesis we crossed MRP8-PML/RARA transgenic mice with BXH-2 mice, which harbor an endogenous retrovirus that causes AML. Approximately half of the leukemias that arose in this cross showed features of acute promyelocytic leukemia (APL). We identified 22 insertions sites in 8 APL-like leukemias. Of these, 7 represented common insertion sites in the Mouse Retroviral Tagged Cancer Gene Database (RTCGD, http://rtcgd.ncifcrf.gov/mm4/index.html). We introduced into a retroviral vector cDNAs encoding 6 genes located at retroviral insertion sites identified in PML/RARA leukemias (Sox4, Meis1, Lck, Sfpi1, Nfil3, Cblb). PML/RARA transgenic bone marrow was transduced with these retroviruses and the marrow was used to reconstitute lethally irradiated recipient animals. Recipients of PML/RARα transgenic marrow transduced with a SOX4 retrovirus developed APL-like leukemias in 3 months. SOX4 is an HMG box transcription factor that exhibits sequence specific DNA binding and transactivation. It is the most common insertion site in RTCGD, and has been found to be overexpressed in small cell lung cancer and medulloblastoma, as well as other tumors. In light of other data indicating that combining transcription factor abnormalities can rapidly induce leukemia (e.g. Hoxa9 + Meis1), our finding that SOX4 + PML/RARα is potently leukemogenic supports the hypothesis that such cooperativity represents another important paradigm in myeloid leukemogenesis.