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Signal transduction based molecular ...

Irish, Jonathan Michael.

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Signal transduction based molecular phenotyping of cancer: Arrayed flow cytometry for discovery of tumor initiation and maintenance mechanisms.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Signal transduction based molecular phenotyping of cancer: Arrayed flow cytometry for discovery of tumor initiation and maintenance mechanisms./
Author:	Irish, Jonathan Michael.
Description:	193 p.
Notes:	Source: Dissertation Abstracts International, Volume: 65-04, Section: B, page: 1791.
Contained By:	Dissertation Abstracts International65-04B.
Subject:	Health Sciences, Oncology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3128652
ISBN:	0496759140

Signal transduction based molecular phenotyping of cancer: Arrayed flow cytometry for discovery of tumor initiation and maintenance mechanisms.
Irish, Jonathan Michael.

Signal transduction based molecular phenotyping of cancer: Arrayed flow cytometry for discovery of tumor initiation and maintenance mechanisms. - 193 p.

Source: Dissertation Abstracts International, Volume: 65-04, Section: B, page: 1791.

Thesis (Ph.D.)--Stanford University, 2004.

Phospho-protein driven signaling networks support altered growth factor responses of tumors and are considered crucial to initiation and maintenance of tumor cell pathology. Knowledge of intracellular signaling differences among tumors could therefore provide the basis for an improved tumor classification system. The work presented in this dissertation demonstrates the scope of dysregulated signal transduction in the context of human leukemic tumors. The considerable variability in the activity of STAT, Ras-MAPK, and p53 pathway phospho-proteins observed in patient material indicates that tumors of similar origin employ different signal transduction strategies to evolve proliferative advantages in the context of apoptosis suppression. This work further demonstrates that phospho-protein profiles can identify patient groups that are likely to relapse following standard anti-proliferative chemotherapy. A molecular mechanism of acute myeloid leukemia (AML) relapse was mapped, using a combination of proteomic techniques, to potentiated Stat5 and Stat3 signaling overexpression in the context of inactivated Stat1, p38, and p53 tumor suppressors. An arrayed flow cytometry technique to detect intracellular antigens, including phosphorylated signaling molecules, was developed and is described. Potentiated STAT signaling was observed specifically in AML blasts where the Flt3 receptor tyrosine kinase was mutated. Furthermore, Bcl-2 overexpression was correlated with STAT signaling in a subset of undifferentiated, CD34+ tumors and was demonstrated to be sufficient to induce p53 hyperphosphorylation. The observation that Bcl-2 expression was coincident with hyperphosphorylation of p53 and a signature pattern of p53 post-translational modification suggests that a role of Bcl-2 in leukemogenesis is inactivation of wild type p53. That signal transduction alterations were common in leukemic blasts that resisted anti-proliferative therapy indicated a potentiated model for tumor signaling that is discussed in detail. This new approach to tumor classification suggests that strategies for therapeutic inhibition of leukemic signal transduction might be effective against tumors with specific phospho-protein biosignatures.

ISBN: 0496759140Subjects--Topical Terms:

1018566
Health Sciences, Oncology.

Signal transduction based molecular phenotyping of cancer: Arrayed flow cytometry for discovery of tumor initiation and maintenance mechanisms.
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