Aldehyde Dehydrogenases Play a Role in Acute Myeloid Leukemia and Have Prognostic and Therapeutic Significance
Bibliographic record
Abstract
Abstract Aldehyde dehydrogenase 1A1 (ALDH1A1) is highly expressed in CD34+ hematopoietic stem cells (HSCs) and functions in part to metabolize ROS and reactive aldehydes, important functions for maintaining the stem cell compartment. In this study we examined the role of ALDH isoforms in acute leukemia. We report here that loss of ALDH1A1, along with a compensatory isoform ALDH3A1, predisposes to acute leukemia in a murine model. Further, approximately 25% of human AMLs were also found to express low levels of ALDH1A1 and ALDH3A1 and this subset has a better outcome to treatment with standard AML therapies. A number of other ALDH isoforms are expressed in AML and higher levels of ALDH7A1 expression correlated with better outcomes particularly when this marker is combined with low-level ALDH1A1 expression. Kasumi-1, a model human ALDH1A1-/3A1- AML cell line, was found to have high levels of intracellular ROS, reactive aldehydes and DNA damage all of which were ameliorated by ALDH1A1 re-expression using lentiviral vector gene transfer. To analyze the variability of ALDH1A1 expression noted in the gene expression studies, 20 primary AML samples were stained with Aldefluor, a fluorescent substrate for ALDH1A1 along with CD34 and CD38 and analyzed by flow cytometry. This revealed further heterogeneity in ALDH activity with 25% of samples having no cells detectable by Aldefluor staining (termed ALDH1A1- AML) and 75% having variable proportions of cells with Aldefluor staining which we grouped into ALDH1A1Low (0.1-1.5% Aldefluor+ cells), ALDH1A1Intermediate (1.6-10% ALDH+ cells) and ALDH1A1high (>10% ALDH+ cells) AMLs. Both Kasumi-1 and ALDH1A1-/3A1- primary AML samples, compared to their ALDH+ counterparts, were highly sensitive to toxic ALDH substrates including 4-HNE and Cyclophosphamide (Cy) and the effects of Cy were potentiated by treatment with Arsenic Trioxide (ATO), and parthenolide (PTL). Similar results were seen when ALDH- and ALDH+ AML cells from the same sample were sorted to purity and treated with 4-HC+ATO. In contrast, normal CD34+ cells were relatively resistant to these agents. Lastly, ALDH3B1 was found to be elevated in many AML samples which had low or absent levels of ALDH1A1 suggesting it may compensate for loss of ALDH1A1 and inhibition of ALDH3B1 also potentiated the toxic effects of Cy and other agents. Together these results demonstrate that several of the ALDHs play an important role in leukemia, expression levels of individual isoforms have important prognostic significance and the absence of the ALDH1A1 isoform in a subset of leukemias may allow the application of targeted therapies that exploit this difference with normal HSCs. Based on our laboratory findings, we propose a clinical study in which AML patients with low/negative ALDH1A1 will be treated with a regimen combining Cy and ATO. Disclosures No relevant conflicts of interest to declare.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".