General AML

Therapeutic strategy for AML patients with loss of ALDH1A1

Aldehyde Dehydrogenase 1A1 (ALDH1A1), an isoform of Aldehyde Dehydrogenase (ALDH), is highly expressed on Hematopoietic Stem Cells (HSCs) and it plays a role in leukemic transformation. ALDH1A1 functions in protecting HSCs by metabolizing Reactive Oxygen Species (ROS) and reactive aldehydes. In Acute Myeloid Leukemia (AML), the presence of isoforms of ALDH has been reported to be associated with poor prognosis.1  

Maura Gasparetto from the University of Colorado, Aurora, and colleagues investigated the significance of ALDH1A1 activity in AML cells. The results of the study were published ahead of print in Haematologica on 9th March 2017.2

The key results of the study were:
  • Using Aldefluor (stains cells expressing high levels of ALDH), low to undetectable levels of expression and activity of ALDH1A1 were observed in AML cells (ALDH1A1- AML) compared to high expression in normal HSCs
  • There was a significant association between good risk cytogenetics and ALDH1A1- AML; P < 0.0001
  • DNA damage and ROS were observed in Kasumi-1 (ALDH1A1- AML cell line) treated with 4-Hydroxynoneal (4HNE; a toxic reactive aldehyde substrate of ALDH1A) compared to normal HSCs which were resistant
  • Treatment of Kasumi-1 cells with Arsenic Trioxide (ATO) and 4-Cyclophosphamide (4HC) led to an increase in apoptosis of ALDH1A1- cells compared to control
  • Treatment of NSGS mice engrafted with MOLM-13 (ALDH1A1- AML cell line) with ATO and Cyclophosphamide (Cy) lead to a reduction of MOLM-13 cells compared to placebo treated mice

In summary, loss of ALDH1A1 renders AML cells more sensitive to chemotherapy and correlates with good cytogenetics.

The authors highlighted that their findings suggest a novel targeted therapy for ALDH1A1- AMLs. They further proposed that ALDH1A1- AMLs “are more sensitive to compounds that directly or indirectly generate toxic ALDH substrates including ROS, reactive aldehydes and others, while normal HSCs with high levels of ALDH1A1 are relatively resistant”.

In conclusion, the authors stated that their findings “provide a rationale for performing phase I/II clinical trial of Cy plus ATO in ALDH1A1- AML patients to determine efficacy and toxicity”.

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.

References
  1. Smith C. et al. Aldehyde dehydrogenases in acute myeloid leukemia. Ann N Y Acad Sci. 2014 Mar 18; 1310: 58–68. DOI: 1111/nyas.12414.
  2. Gasparetto M. et al. Targeted Therapy For A Subset Of Acute Myeloid Leukemias That Lack Expression Of Aldehyde Dehydrogenase 1A1. Haematologica. 2017 Mar 9. DOI: 3324/haematol.2016.159053. [Epub ahead of print].
Download this article:

You can now download this article in Adobe PDF® format.

Download as PDF