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Targeting the TAM Receptors in Leukemia


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1

Aflac Cancer Center of Children’s Healthcare of Atlanta, Department of Pediatrics, Emory University, Atlanta, GA 30322, USA

2

UNC Lineberger Comprehensive Cancer Center, Departments of Medicine and Pharmacology, University of North Carolina, Chapel Hill, NC 27514, USA



These authors contributed equally to this work.





*

Author to whom correspondence should be addressed.



Academic Editors: Deric L. Wheeler and Toni M. Brand

Abstract Targeted inhibition of members of the TAM TYRO-3, AXL, MERTK family of receptor tyrosine kinases has recently been investigated as a novel strategy for treatment of hematologic malignancies. The physiologic functions of the TAM receptors in innate immune control, natural killer NK cell differentiation, efferocytosis, clearance of apoptotic debris, and hemostasis have previously been described and more recent data implicate TAM kinases as important regulators of erythropoiesis and megakaryopoiesis. The TAM receptors are aberrantly or ectopically expressed in many hematologic malignancies including acute myeloid leukemia, B- and T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, and multiple myeloma. TAM receptors contribute to leukemic phenotypes through activation of pro-survival signaling pathways and interplay with other oncogenic proteins such as FLT3, LYN, and FGFR3. The TAM receptors also contribute to resistance to both cytotoxic chemotherapeutics and targeted agents, making them attractive therapeutic targets. A number of translational strategies for TAM inhibition are in development, including small molecule inhibitors, ligand traps, and monoclonal antibodies. Emerging areas of research include modulation of TAM receptors to enhance anti-tumor immunity, potential roles for TYRO-3 in leukemogenesis, and the function of the bone marrow microenvironment in mediating resistance to TAM inhibition. View Full-Text

Keywords: TYRO3; AXL; MERTK; Gas6; leukemia; multiple myeloma; tyrosine kinase inhibitor; resistance; hematopoiesis; signaling pathways TYRO3; AXL; MERTK; Gas6; leukemia; multiple myeloma; tyrosine kinase inhibitor; resistance; hematopoiesis; signaling pathways





Autor: Madeline G. Huey 1,†, Katherine A. Minson 1,†, H. Shelton Earp 2, Deborah DeRyckere 1 and Douglas K. Graham 1,*

Fuente: http://mdpi.com/



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