AML1-ETO Fusion Protein up-Regulates TRKA mRNA Expression in Human CD34+Cells, Allowing Nerve Growth Factor-Induced Expansion

• Published in: Proceedings of the National Academy of Sciences - PNAS 2005-03, Vol.102 (11), p.4016-4021
• Main Authors: Mulloy, James C., Jankovic, Vladimir, Wunderlich, Mark, Delwel, Ruud, Cammenga, Jorg, Krejci, Ondrej, Zhao, Hui, Peter J. M. Valk, Lowenberg, Bob, Nimer, Stephen D., Rowley, Janet D.
• Format: Article
• Language: English
• Subjects: Antigens, CD34 - immunology; Biological Sciences; Cell Division - physiology; Cell growth; Cell lines; Cellular biology; Core Binding Factor Alpha 2 Subunit; Cultured cells; Cytokines; Gene expression; Gene Expression Regulation - physiology; Genes; Hematopoietic stem cells; Hematopoietic Stem Cells - immunology; Hematopoietic Stem Cells - metabolism; Hematopoietic Stem Cells - physiology; Humans; Leukemia; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - immunology; Leukemia, Myeloid, Acute - metabolism; Messenger RNA; Myeloid leukemia; Nerve Growth Factor - metabolism; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; Proteins; Quantitative genetics; Receptor, trkA - biosynthesis; Receptor, trkA - genetics; RUNX1 Translocation Partner 1 Protein; Stem cells; Stromal cells; Transcription Factors - genetics; Transcription Factors - metabolism; Translocation, Genetic; Up-Regulation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0404701102

The AML1-ETO fusion protein, generated by the t(8;21) in acute myeloid leukemia (AML), exerts dominant-negative functions and a variety of gains of function, including a positive effect on the growth of primary human CD34+hematopoietic stem/progenitor cells. We now show that AML1-ETO expression up-regulates the level of TRKA mRNA and protein in these cells and that AML1-ETO-expressing CD34+hematopoietic cells grown in the presence of five early-acting hematopoietic cytokines further proliferate in response to nerve growth factor (NGF). These cells also show a unique response to NGF and IL-3; namely, they expand in liquid culture. To determine the biological relevance of our findings, we analyzed 262 primary AML patient samples using real-time RT-PCR and found that t(8;21)-positive AML samples express significantly higher levels of TRKA mRNA than other subtypes of AML. NGF, which is normally expressed by bone marrow stromal cells, could provide important proliferative or survival signals to AML1-ETO-expressing leukemic or preleukemic cells, and the NGF/TRKA signaling pathway may be a suitable target for therapeutic approaches to AML.