TY - JOUR A1 - Oancea, Claudia A1 - Rüster, Brigitte Inge A1 - Brill, Boris A1 - Roos, Jessica A1 - Heinssmann, Maria A1 - Bug, Gesine A1 - Mian, Afsar Ali A1 - Guillen, Nathalie Andrea A1 - Kornblau, Steven M. A1 - Henschler, Reinhard A1 - Ruthardt, Martin T1 - STAT activation status differentiates leukemogenic from non-leukemogenic stem cells in AML and is suppressed by arsenic in t(6;9)-positive AML T2 - Genes & cancer N2 - Acute myeloid leukemia (AML) is characterized by an aberrant self-renewal of hematopoietic stem cells (HSC) and a block in differentiation. The major therapeutic challenge is the characterization of the leukemic stem cell as a target for the eradication of the disease. Until now the biology of AML-associated fusion proteins (AAFPs), such as the t(15;17)-PML/RARα, t(8;21)-RUNX1/RUNX1T1 and t(6;9)-DEK/NUP214, all able to induce AML in mice, was investigated in different models and genetic backgrounds, not directly comparable to each other. To avoid the bias of different techniques and models we expressed these three AML-inducing oncogenes in an identical genetic background and compared their influence on the HSC compartment in vitro and in vivo. These AAFPs exerted differential effects on HSCs and PML/RARα, similar to DEK/NUP214, induced a leukemic phenotype from a small subpopulation of HSCs with a surface marker pattern of long-term HSC and characterized by activated STAT3 and 5. In contrast the established AML occurred from mature populations in the bone marrow. The activation of STAT5 by PML/RARα and DEK/NUP214 was confirmed in t(15;17)(PML/RARα) and t(6;9)(DEK/NUP214)-positive patients as compared to normal CD34+ cells. The activation of STAT5 was reduced upon the exposure to Arsenic which was accompanied by apoptosis in both PML/RARα- and DEK/NUP214-positive leukemic cells. These findings indicate that in AML the activation of STATs plays a decisive role in the biology of the leukemic stem cell. Furthermore we establish exposure to arsenic as a novel concept for the treatment of this high risk t(6;9)-positive AML. KW - leukemia initiating cell KW - t(6;9) KW - STAT5 KW - arsenic trioxide Y1 - 2014 UR - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/57413 UR - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-574134 SN - 1947-6027 SN - 1947-6019 VL - 5 IS - 11-12 SP - 378 EP - 392 PB - Impact Journals LLC CY - Orchard Park, NY ER -