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Haematologica. 2017 Mar 9. pii: haematol.2016.159053. doi: 10.3324/haematol.2016.159053. [Epub ahead of print]

Targeted therapy for a subset of acute myeloid leukemias that lack expression of aldehyde dehydrogenase 1A1.

Author information

1
Division of Hematology, University of Colorado, Aurora, Colorado, USA; maura.gasparetto@ucdenver.edu.
2
Division of Hematology, University of Colorado, Aurora, Colorado, USA.
3
Genomics Research Center, University of Rochester, Rochester, New York, USA.
4
Department of Medicine, University of Rochester Medical Center, Rochester, New York, USA.
5
Department of Environmental Health Sciences, Yale University, New Haven, Connecticut, USA.
6
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.

Abstract

Aldehyde dehydrogenase 1A1 (ALDH1A1) activity is high in hematopoietic stem cells and functions in part to protect stem cells from reactive aldehydes and other toxic compounds. In contrast, we found that ~25% of all acute myeloid leukemias expressed low or undetectable levels of ALDH1A1 and that this ALDH1A1- subset of leukemias correlates with good prognosis cytogenetics. ALDH1A1- cell lines as well as primary leukemia cells were found to be sensitive to treatment with compounds that directly and indirectly generate toxic ALDH substrates including 4-hydroxynonenal and the clinically relevant compounds arsenic trioxide and 4-hydroperoxycyclophosphamide. In contrast, normal hematopoietic stem cells were relatively resistant to these compounds. Using a murine xenotransplant model to emulate a clinical treatment strategy, established ALDH1A1- leukemias were also sensitive to in vivo treatment with cyclophosphamide combined with arsenic trioxide. These results demonstrate that targeting ALDH1A1- leukemic cells with toxic ALDH1A1 substrates such as arsenic and cyclophosphamide may be a novel targeted therapeutic strategy for this subset of acute myeloid leukemias.

KEYWORDS:

ALDH1A1; ALDHs; AML; Acute Myeloid Leukemia; Leukemic Stem Cell

PMID:
28280079
DOI:
10.3324/haematol.2016.159053
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