Oncotarget

Research Papers:

Potential for subsets of wt-NPM1 primary AML blasts to respond to retinoic acid treatment

Rodica P. Bunaciu, Robert J. MacDonald, Feng Gao, Lynn M. Johnson, Jeffrey D. Varner, Xin Wang, Sarah Nataraj, Monica L. Guzman and Andrew Yen _

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Oncotarget. 2018; 9:4134-4149. https://doi.org/10.18632/oncotarget.23642

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Abstract

Rodica P. Bunaciu1, Robert J. MacDonald1, Feng Gao1,4,5, Lynn M. Johnson3, Jeffrey D. Varner4, Xin Wang5, Sarah Nataraj2, Monica L. Guzman2 and Andrew Yen1

1Department of Biomedical Sciences, Cornell University, Ithaca, NY, USA

2Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY, USA

3Cornell Statistical Unit, Cornell University, Ithaca, NY, USA

4Robert Frederick Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY, USA

5Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China

Correspondence to:

Andrew Yen, email: [email protected], [email protected]

Keywords: retinoic acid; c-Raf; c-Cbl; AML; precision oncology

Received: October 16, 2017     Accepted: December 09, 2017     Published: December 23, 2017

ABSTRACT

Acute myeloid leukemia (AML) has high mortality rates, perhaps reflecting a lack of understanding of the molecular diversity in various subtypes and a lack of known actionable targets. There are currently 12 open clinical trials for AML using combination therapeutic modalities including all-trans retinoic acid (RA). Mutant nucleophosmin-1, proposed as a possible marker for RA response, is the criterion for recruiting patients in three active RA phase 3 clinical trials. We tested the ability of RA alone or in combination with either bosutinib (B) or 6-formylindolo(3,2-b) carbazole (F) to induce conversion of 12 de novo AML samples toward a more differentiated phenotype. We assessed levels of expression of cell surface markers associated with differentiation, aldehyde dehydrogenase activity, and glucose uptake activity. Colony formation capacity was reduced with the combined treatment of RA and B or F, and correlated with modulation of a c-Cbl/Lyn/c-Raf-centered signalsome. Combination treatment was in most cases more effective than RA alone. Based on their responses to the treatments, some primary leukemic samples cluster closer to HL-60 cells than to other primary samples, suggesting that they may represent a hitherto undefined AML subtype that is potentially responsive to RA in a combination differentiation therapy.


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