Oncotarget

Research Papers:

Characterization of TRKA signaling in acute myeloid leukemia

Shelley M. Herbrich, Sankaranarayanan Kannan, Riitta M. Nolo, Marisa Hornbaker, Joya Chandra and Patrick A. Zweidler-McKay _

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Oncotarget. 2018; 9:30092-30105. https://doi.org/10.18632/oncotarget.25723

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Abstract

Shelley M. Herbrich1, Sankaranarayanan Kannan2, Riitta M. Nolo2, Marisa Hornbaker1, Joya Chandra2 and Patrick A. Zweidler-McKay3

1Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America

2Department of Pediatrics, University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America

3Immunogen, Inc., Waltham, Massachuessettes, United States of America

Correspondence to:

Patrick A. Zweidler-McKay, email: Patrick.Zweidler-McKay@ImmunoGen.com

Keywords: Acute Myeloid Leukemia (AML); NGF/TRKA signaling; leukemogenesis

Received: April 18, 2018    Accepted: June 19, 2018    Published: July 10, 2018

ABSTRACT

Tropomyosin-related kinase A (TRKA) translocations have oncogenic potential and have been found in rare cases of solid tumors. Accumulating evidence indicates that TRKA and its ligand, nerve growth factor (NGF), may play a role in normal hematopoiesis and may be deregulated in leukemogenesis. Here, we report a comprehensive evaluation of TRKA signaling in normal and leukemic cells. TRKA expression is highest in common myeloid progenitors and is overexpressed in core binding factor and megakaryocytic leukemias, especially Down syndrome-related AML. Importantly, NGF can rescue GM-CSF dependent TF-1 AML cells, but does not drive proliferation in other TRKA-expressing lines. Although TRKA expression is heterogeneous between and within AML samples, NGF stimulation broadly induces ERK signaling, demonstrating the functional ability of AML cells to respond to NGF/TRKA signaling. However, neither shRNA knockdown nor pharmacologic inhibition have significant anti-proliferative effects on human AML cells in vitro and in vivo. Thus, despite functional NGF/TRKA signaling, the importance of TRKA in AML remains unclear.


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