Targeting receptor tyrosine kinase signaling in acute myeloid leukemia

Abstract

Targeting receptor tyrosine kinase signaling in acute myeloid leukemia The main goal of this work was therefore aimed at gaining deeper insight into RTK signaling in a panel of AML cell lines and patient blast cells. A broad potein expression analysis was set up in order to identify cancer-specific expression patterns of signaling molecules and to uncover potential molecular targets. Using different approaches the molecular function and the feasibility of targeting the candidate proteins was investigated. Novel specific inhibitors were tested and neutralizing antibodies and RNA interference (RNAi) were used to block or down-regulate the individual proteins. Our study of the IGF-IR/PI3K signaling system in AML cells uncovered a novel role for autocrine IGF-I signaling in the growth and survival of these cancer cells. Besides, we could show that targeting this signaling branch in combination with commonly used chemotherapeutical agents represents an interesting novel approach for AML therapy.As protein expression analysis revealed highly variable expression levels of the mammalian target of rapamycin (mTOR) in the panel of cells analyzed, further interest was laid on the role of mTOR in AML. Cells expressing low levels of mTOR were compared to cells expressing high levels of this protein and a siRNA screen was aimed at uncovering human kinases that modulate the sensitivity to the mTOR inhibitor rapamycin. Preliminary results suggest that mTOR plays a crucial role in cell growth and survival in a subset of AML cells and that rapamycin in combination with certain RTK or Syk/ZAP70 inhibitors has potential for AML therapy. In summary, our study of the RTK/PI3K signaling system in distinct human cancers has provided novel insights into the importance and the complexity of this network for tumor growth and survival. Moreover, the analysis of specific components of this crucial signaling network has uncovered potential molecular targets for future cancer therapy.

Inhibition of Class I Phosphoinositide 3-Kinase Activity Impairs Proliferation and Triggers Apoptosis in Acute Promyelocytic Leukemia without Affecting Atra-Induced Differentiation

“…In malignant hematologic disease, PI3K signaling is most likely activated by oncogenic mutations of upstream regulators such as tyrosine kinases and Ras (38) and/or autocrine growth factor loops (21). Of the different PI3K isoforms, it has been shown that p110y plays an important role in cell proliferation, survival, and chemoresistance in AML (28,29).…”

Common Leukemia- and Lymphoma-Associated Genetic Aberrations in Healthy Individuals

“…It has been proposed that two major genetic events are involved in leukemic transformation. 30 The core of this theory is that two separate mutations or two groups of mutations must arise at approximately the same time for leukemia to develop. One mutation leads to the proliferation of the hematopoietic progenitors.…”

RNA Trafficking by Acute Myelogenous Leukemia Exosomes

“…A sample in PBS buffer was loaded into a quartz cuvette and analyzed with a 488 nm laser. Fifty spectra were collected at 25 C to estimate diffusion coefficient and relative polydispersity. Data were analyzed with Dynamics software V.5.25.44 (Protein Solutions) and vesicle size was measured as the mean hydrodynamic radius.…”