Therapeutic targeting of the MEK/MAPK signal transduction module in acute myeloid leukemia

Milella, Michele Stanislaw; Kornblau, Steven M.; Estrov, Zeev; Carter, Bing Z.; Lapillonne, Hélène; Harris, David; Konopleva, Marina; Zhao, Shourong; Estey, Elihu H.; Andreeff, Michael

doi:10.1172/jci200112807

Cited by 142 publications

(213 citation statements)

References 33 publications

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“…40,41 In leukemia cells, blockade of the PI3K or ERK signaling pathway enhances apoptosis in response to antileukemic drugs such as arsenic trioxide or histone deacetylase inhibitors. [42][43][44] It is well established that exogenous HMGB1 induces MEK-ERK activation in immune cells and cancer cells. 19,22,32,45 Here, we found that 3-MA inhibited HMGB1-induced phosphorylation of ERK, indicating that ERK is a downstream signal of PI3K.…”

Section: Discussionmentioning

confidence: 99%

HMGB1-induced autophagy promotes chemotherapy resistance in leukemia cells

et al. 2010

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Autophagy, a tightly regulated lysosome-dependent catabolic pathway, is important in the regulation of cancer development and progression and in determining the response of tumor cells to anticancer therapy. However, the role of autophagy in leukemia still remains largely unknown. Here we show that high-mobility group box 1 (HMGB1), the best characterized damage-associated molecular pattern, was released from leukemia cell lines after chemotherapy-induced cytotoxicity and activated autophagy to protect against injury. Treatment with HMGB1-neutralizing antibodies increased the sensitivity of leukemia cells to chemotherapy; whereas, exogenous HMGB1 rendered these cells more resistant to drug-induced cytotoxicity. Moreover, exogenous HMGB1 increased autophagy as evaluated by increased expression of the autophagic marker microtubule-associated protein light chain 3-II, degradation of sequestosome 1 (p62) and autophagosome formation. Furthermore, knockdown or pharmacological inhibition of either phosphoinositide 3-kinase-III or extracellular signal-regulated kinase kinase mitogen-activated protein kinase kinase/extracellular signal-regulated protein kinase inhibited HMGB1-induced autophagy. Taken together, these results suggest that HMGB1 release after chemotherapy is a critical regulator of autophagy and a potential drug target for therapeutic interventions in leukemia.

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Section: Discussionmentioning

confidence: 99%

HMGB1-induced autophagy promotes chemotherapy resistance in leukemia cells

et al. 2010

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“…It has been reported that mTOR activity could be controlled through the Erk pathway. [40][41][42] As constitutive Erk activation is seen in a majority of clinical AML specimens as well as in HL-60 cells, 43 activation of the Raf/Mek/Erk pathway could mediate 4E-BP1 phosphorylation independent of the status of the PI3K/Akt/mTOR signaling. Identification of predictive biomarkers for PI-103 would allow identification of patients who are most likely to benefit from dual PI3K/mTOR inhibition.…”

Section: Discussionmentioning

confidence: 99%

The dual PI3 kinase/mTOR inhibitor PI-103 prevents p53 induction by Mdm2 inhibition but enhances p53-mediated mitochondrial apoptosis in p53 wild-type AML

et al. 2008

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Activation of the phosphatidylinositol-3 kinase/Akt/mammalian target of the rapamycin (PI3K/Akt/mTOR) pathway and inactivation of wild-type p53 by murine double minute 2 homologue (Mdm2) overexpression are frequent molecular events in acute myeloid leukemia (AML). We investigated the interaction of PI3K/Akt/mTOR and p53 pathways after their simultaneous blockade using the dual PI3K/mTOR inhibitor PI-103 and the Mdm2 inhibitor Nutlin-3. We found that PI-103, which itself has modest apoptogenic activity, acts synergistically with Nutlin-3 to induce apoptosis in a wild-type p53-dependent fashion. PI-103 synergized with Nutlin-3 to induce Bax conformational change and caspase-3 activation, despite its inhibitory effect on p53 induction. The PI-103/Nutlin-3 combination caused profound dephosphorylation of 4E-BP1 and decreased expression of many proteins including Mdm2, p21, Noxa, Bcl-2 and survivin, which can affect mitochondrial stability. We suggest that PI-103 actively enhances downstream p53 signaling and that a combination strategy aimed at inhibiting PI3K/Akt/mTOR signaling and activating p53 signaling is potentially effective in AML, where TP53 mutations are rare and downstream p53 signaling is intact.

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“…10,11 Upregulation of the Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/ mTOR pathways and phosphorylation of the downstream target Bad are observed frequently in AML patient specimens and associated with a poorer prognosis than patients lacking these changes. [11][12][13][14][15][16] Aberrant expression of multiple signaling pathways is associated with a worse prognosis. 13 FLT3 ITD mutations are present in 20-30% of AMLs, and these patients have a poorer prognosis than patients lacking these mutations.…”

Section: Signaling Pathways and Hematopoietic Cancermentioning

confidence: 99%