التفاصيل البيبلوغرافية
| العنوان: |
Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. |
| المؤلفون: |
Schenk, Tino, Chen, Weihsu Claire, Göllner, Stefanie, Howell, Louise, Jin, Liqing, Hebestreit, Katja, Klein, Hans-Ulrich, Popescu, Andreea C, Burnett, Alan, Mills, Ken, Casero, Robert A, Marton, Laurence, Woster, Patrick, Minden, Mark D, Dugas, Martin, Wang, Jean C Y, Dick, John E, Müller-Tidow, Carsten, Petrie, Kevin, Zelent, Arthur |
| المصدر: |
Nature Medicine; Apr2012, Vol. 18 Issue 4, p605-611, 7p, 4 Graphs |
| مصطلحات موضوعية: |
ACUTE promyelocytic leukemia, DEMETHYLASE, TRETINOIN, TRANYLCYPROMINE, SEVERE combined immunodeficiency |
| مستخلص: |
Acute promyelocytic leukemia (APL), a cytogenetically distinct subtype of acute myeloid leukemia (AML), characterized by the t(15;17)-associated PML-RARA fusion, has been successfully treated with therapy utilizing all-trans-retinoic acid (ATRA) to differentiate leukemic blasts. However, among patients with non-APL AML, ATRA-based treatment has not been effective. Here we show that, through epigenetic reprogramming, inhibitors of lysine-specific demethylase 1 (LSD1, also called KDM1A), including tranylcypromine (TCP), unlocked the ATRA-driven therapeutic response in non-APL AML. LSD1 inhibition did not lead to a large-scale increase in histone 3 Lys4 dimethylation (H3K4me2) across the genome, but it did increase H3K4me2 and expression of myeloid-differentiation-associated genes. Notably, treatment with ATRA plus TCP markedly diminished the engraftment of primary human AML cells in vivo in nonobese diabetic (NOD)-severe combined immunodeficient (SCID) mice, suggesting that ATRA in combination with TCP may target leukemia-initiating cells. Furthermore, initiation of ATRA plus TCP treatment 15 d after engraftment of human AML cells in NOD-SCID ? (with interleukin-2 (IL-2) receptor ? chain deficiency) mice also revealed the ATRA plus TCP drug combination to have a potent anti-leukemic effect that was superior to treatment with either drug alone. These data identify LSD1 as a therapeutic target and strongly suggest that it may contribute to AML pathogenesis by inhibiting the normal pro-differentiative function of ATRA, paving the way for new combinatorial therapies for AML. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |
