Page 173 - Haematologica March 2020

Acute Myeloid Leukemia
The novel Isatin analog KS99 targets stemness markers in acute myeloid leukemia
Ferrata Storti Foundation
Haematologica 2020 Volume 105(3):687-696
Charyguly Annageldiyev,1,2 Krishne Gowda,2,3 Trupti Patel,4
Priyanjali Bhattacharya,4 Su-Fern Tan,5 Soumya Iyer,6 Dhimant Desai,2,3
Sinisa Dovat,6 David J. Feith,5,7 Thomas P. Loughran Jr.,5,7 Shantu Amin,2,3 David Claxton1,2 and Arati Sharma1,2,3
1Department of Medicine, Division of Hematology and Oncology, Pennsylvania State University College of Medicine, Hershey, PA, USA; 2Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA, USA; 3Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, USA; 4Department of Integrative Biotechnology, SBST, VIT Vellore, Tamilnadu, India; 5Department of Medicine, Division of Hematology and Oncology, University of Virginia School of Medicine, Charlottesville, VA, USA; 6Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA, USA and 7University of Virginia Cancer Center, Charlottesville, VA, USA
ABSTRACT
Leukemic stem cells are multipotent, self-renewing, highly proliferative cells that can withstand drug treatments. Although currently available treatments potentially destroy blast cells, they fail to eradicate leukemic progenitor cells completely. Aldehyde dehydrogenase and STAT3 are frequently up-regulated in pre-leukemic stem cells as well as in acute myeloid leukemia (AML) expressing the CD34+CD38– phenotype. The Isatin analog, KS99 has shown anticancer activity against multiple myelo- ma which may, in part, be mediated by inhibition of Bruton’s tyrosine kinase activation. Here we demonstrate that KS99 selectively targets leukemic stem cells with high aldehyde dehydrogenase activity and inhibits phosphorylation of STAT3. KS99 targeted cells co-expressing CD34, CD38, CD123, TIM-3, or CD96 immunophenotypes in AML, alone or in combi- nation with the standard therapeutic agent cytarabine. AML with myelodysplastic-related changes was more sensitive than de novo AML with or without NPM1 mutation. KS99 treatment reduced the clonogenicity of primary human AML cells as compared to normal cord blood mononuclear cells. Downregulation of phosphorylated Bruton’s tyrosine kinase, STAT3, and aldehyde dehydrogenase was observed, suggesting interaction with KS99 as predicted through docking. KS99 with or without cytarabine showed in vivo preclinical efficacy in human and mouse AML animal mod- els and prolonged survival. KS99 was well tolerated with overall negligible adverse effects. In conclusion, KS99 inhibits aldehyde dehydrogenase and STAT3 activities and causes cell death of leukemic stem cells, but not nor- mal hematopoietic stem and progenitor cells.
Introduction
Acute myeloid leukemia (AML) is a heterogeneous disease with treatment rely- ing primarily on traditional cytotoxic agents and hematopoietic stem cell transplan- tation. AML arises from hematopoietic stem and progenitor cells (HSPC) through various alterations in stem cells.1 During blast transformation, mutant progenitors undergo stepwise genetic, epigenetic and clonal changes, and give rise to pre- leukemia stem cells (pre-LSC) as well as fully transformed leukemia stem cells (LSC).2 These cells are frequently chemo-resistant, and their division leads to clon- ally aggressive AML.1 Thus, effective therapies are warranted to destroy AML stem cells selectively, but not normal HSPC. While LSC were initially defined as cells with CD34+CD38– phenotype with ability to engraft in mouse models,2-5 recent data have demonstrated CD34+CD38+ AML cells also have an engraftment poten-
Correspondence:
ARATI SHARMA
asharma@pennstatehealth.psu.edu
Received: November 24, 2018. Accepted: May 22, 2019. Pre-published: May 23, 2019.
doi:10.3324/haematol.2018.212886
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/3/687
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haematologica | 2020; 105(3)
687
ARTICLE