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Haematologica. 2019 May 23. pii: haematol.2018.212886. doi: 10.3324/haematol.2018.212886. [Epub ahead of print]

The novel Isatin analog KS99 targets stemness markers in acute myeloid leukemia.

Author information

1
Department of Medicine, Pennsylvania State University College of Medicine, Hershey, PA, USA.
2
Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, USA.
3
Department of Integrative Biotechnology, SBST, VIT Vellore, Tamilnadu, India.
4
Dept. of Medicine, University of Virginia School of Medicine, Charlottesville, VA.
5
Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA, USA.
6
Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, USA; asharma@pennstatehealth.psu.edu.

Abstract

Leukemic stem cells are multipotent, self-renewing, highly proliferative cells that can withstand drug treatments. Although presently 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 expressing CD34+CD38- phenotype. The Isatin analog, KS99 has shown anticancer activity against multiple myeloma 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 coexpressing CD34, CD38, CD123, TIM-3, or CD96 immunophenotypes in acute myeloid leukemia, alone or in combination with the standard therapeutic agent cytarabine. Acute myeloid leukemia with myelodysplastic-related changes was more sensitive than De Novo acute myeloid leukemia with or without NPM1 mutation. KS99 treatment reduced the clonogenicity of primary human acute myeloid leukemia cells as compared to normal cord blood mononuclear cells. Down-regulation of phosphorylated Bruton's tyrosine kinase, STAT3, and aldehyde dehydrogenase was observed, suggesting interaction with KS99 as predicated through docking. KS99 with or without cytarabine showed in vivo preclinical efficacy in human and mouse acute myeloid leukemia animal models and prolonged the survival. KS99 was well tolerated with an overall negligible adverse effect. In conclusion, KS99 inhibits aldehyde dehydrogenase and STAT3 activity and causes cell death leukemic stem cells, but not normal hematopoietic stem and progenitor cells.

KEYWORDS:

ALDH; BTK; Immunophenotyping; Leukemic Stem Cell; STAT3

PMID:
31123028
DOI:
10.3324/haematol.2018.212886
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