Effects of p38α/β inhibition on acute lymphoblastic leukemia proliferation and survival in vivo
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Effects of p38α/β inhibition on acute lymphoblastic leukemia proliferation and survival in vivo. / Alsadeq, A; Strube, S; Krause, S; Carlet, M; Jeremias, I; Vokuhl, C; Loges, S; Aguirre-Ghiso, J A; Trauzold, A; Cario, G; Stanulla, M; Schrappe, M; Schewe, D M.
In: LEUKEMIA, Vol. 29, No. 12, 29.12.2015, p. 2307-16.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Effects of p38α/β inhibition on acute lymphoblastic leukemia proliferation and survival in vivo
AU - Alsadeq, A
AU - Strube, S
AU - Krause, S
AU - Carlet, M
AU - Jeremias, I
AU - Vokuhl, C
AU - Loges, S
AU - Aguirre-Ghiso, J A
AU - Trauzold, A
AU - Cario, G
AU - Stanulla, M
AU - Schrappe, M
AU - Schewe, D M
PY - 2015/12/29
Y1 - 2015/12/29
N2 - P38α/β has been described as a tumor-suppressor controlling cell cycle checkpoints and senescence in epithelial malignancies. However, p38α/β also regulates other cellular processes. Here, we describe a role of p38α/β as a regulator of acute lymphoblastic leukemia (ALL) proliferation and survival in experimental ALL models. We also report first evidence that p38α/β phosphorylation is associated with the occurrence of relapses in TEL-AML1-positive leukemia. First, in vitro experiments show that p38α/β signaling is induced in a cyclical manner upon initiation of proliferation and remains activated during log-phase of cell growth. Next, we provide evidence that growth-permissive signals in the bone marrow activate p38α/β in a novel avian ALL model, in which therapeutic targeting can be tested. We further demonstrate that p38α/β inhibition by small molecules can suppress leukemic expansion and prolong survival of mice bearing ALL cell lines and primary cells. Knockdown of p38α strongly delays leukemogenesis in mice xenografted with cell lines. Finally, we show that in xenografted TEL-AML1 patients, ex vivo p38α/β phosphorylation is associated with an inferior long-term relapse-free survival. We propose p38α/β as a mediator of proliferation and survival in ALL and show first preclinical evidence for p38α/β inhibition as an adjunct approach to conventional therapies.
AB - P38α/β has been described as a tumor-suppressor controlling cell cycle checkpoints and senescence in epithelial malignancies. However, p38α/β also regulates other cellular processes. Here, we describe a role of p38α/β as a regulator of acute lymphoblastic leukemia (ALL) proliferation and survival in experimental ALL models. We also report first evidence that p38α/β phosphorylation is associated with the occurrence of relapses in TEL-AML1-positive leukemia. First, in vitro experiments show that p38α/β signaling is induced in a cyclical manner upon initiation of proliferation and remains activated during log-phase of cell growth. Next, we provide evidence that growth-permissive signals in the bone marrow activate p38α/β in a novel avian ALL model, in which therapeutic targeting can be tested. We further demonstrate that p38α/β inhibition by small molecules can suppress leukemic expansion and prolong survival of mice bearing ALL cell lines and primary cells. Knockdown of p38α strongly delays leukemogenesis in mice xenografted with cell lines. Finally, we show that in xenografted TEL-AML1 patients, ex vivo p38α/β phosphorylation is associated with an inferior long-term relapse-free survival. We propose p38α/β as a mediator of proliferation and survival in ALL and show first preclinical evidence for p38α/β inhibition as an adjunct approach to conventional therapies.
U2 - 10.1038/leu.2015.153
DO - 10.1038/leu.2015.153
M3 - SCORING: Journal article
C2 - 26104660
VL - 29
SP - 2307
EP - 2316
JO - LEUKEMIA
JF - LEUKEMIA
SN - 0887-6924
IS - 12
ER -