High aldehyde dehydrogenase activity at diagnosis predicts relapse in patients with t(8;21) acute myeloid leukemia

Yang, Lu; Chen, Wenmin; Dao, Feng‐Ting; Zhang, Yan‐Huan; Wang, Yazhe; Chang, Yan; Liu, Yanrong; Jiang, Qian; Zhang, Xiao-Hui; Liu, Kai-Yan; Huang, Xiao‐Jun; Qin, Ya‐Zhen

doi:10.1002/cam4.2422

Cited by 7 publications

(4 citation statements)

References 34 publications

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“…Several studies have identified a specific subset of LSCs with high ALDH expression that are quiescent and resistant to chemotherapy [ 58 – 60 ]. In addition, patients with a high percentage of ALDH + LSCs are associated with a poor prognosis and adverse clinical outcomes [ 61 , 62 ]. An assessment of the ALDH level in KG1a cells in classical 2D cultures did not show any significant difference with respective controls (Figure S7 ), but KG1a cells in the 3D mono-culture model did, with a Chi-square value of around 15 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Fabrication of a three-dimensional bone marrow niche-like acute myeloid Leukemia disease model by an automated and controlled process using a robotic multicellular bioprinting system

Alhattab,

Isaioglou,

Alshehri

et al. 2023

Biomater Res

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Background Acute myeloid leukemia (AML) is a hematological malignancy that remains a therapeutic challenge due to the high incidence of disease relapse. To better understand resistance mechanisms and identify novel therapies, robust preclinical models mimicking the bone marrow (BM) microenvironment are needed. This study aimed to achieve an automated fabrication process of a three-dimensional (3D) AML disease model that recapitulates the 3D spatial structure of the BM microenvironment and applies to drug screening and investigational studies. Methods To build this model, we investigated a unique class of tetramer peptides with an innate ability to self-assemble into stable hydrogel. An automated robotic bioprinting process was established to fabricate a 3D BM (niche-like) multicellular AML disease model comprised of leukemia cells and the BM’s stromal and endothelial cellular fractions. In addition, monoculture and dual-culture models were also fabricated. Leukemia cell compatibility, functionalities (in vitro and in vivo), and drug assessment studies using our model were performed. In addition, RNAseq and gene expression analysis using TaqMan arrays were also performed on 3D cultured stromal cells and primary leukemia cells. Results The selected peptide hydrogel formed a highly porous network of nanofibers with mechanical properties similar to the BM extracellular matrix. The robotic bioprinter and the novel quadruple coaxial nozzle enabled the automated fabrication of a 3D BM niche-like AML disease model with controlled deposition of multiple cell types into the model. This model supported the viability and growth of primary leukemic, endothelial, and stromal cells and recapitulated cell-cell and cell-ECM interactions. In addition, AML cells in our model possessed quiescent characteristics with improved chemoresistance attributes, resembling more the native conditions as indicated by our in vivo results. Moreover, the whole transcriptome data demonstrated the effect of 3D culture on enhancing BM niche cell characteristics. We identified molecular pathways upregulated in AML cells in our 3D model that might contribute to AML drug resistance and disease relapse. Conclusions Our results demonstrate the importance of developing 3D biomimicry models that closely recapitulate the in vivo conditions to gain deeper insights into drug resistance mechanisms and novel therapy development. These models can also improve personalized medicine by testing patient-specific treatments. Graphical Abstract

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Section: Resultsmentioning

confidence: 99%

Fabrication of a three-dimensional bone marrow niche-like acute myeloid Leukemia disease model by an automated and controlled process using a robotic multicellular bioprinting system

Alhattab,

Isaioglou,

Alshehri

et al. 2023

Biomater Res

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“…In AML, high aldehyde dehydrogenase activity at diagnosis predicts relapse in patients with t(8;21) AML [40]. In general, evidence has been mounting that the protein family of the aldehyde dehydrogenases plays a role in the development of AML; yet the interpretation of their exact biological effect on AML progression remains debatable [41].…”

Section: Aldh Activity In Acute Leukemiamentioning

confidence: 99%

Aldehyde Dehydrogenase Enzyme Functions in Acute Leukemia Stem Cells

Dancik¹,

Voutsas²,

Vlahopoulos³

2022

Front. Biosci. (Schol Ed)

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The enzymes that belong to the aldehyde dehydrogenase family are expressed in a variety of cells; yet activity of their main members characterizes stem cells, both normal and malignant. Several members of this family perform critical functions in stem cells, in general, and a few have been shown to have key roles in malignant tumors and their recurrence. In particular, ALDH1A1, which localizes to the cytosol and the nucleus, is an enzyme critical in cancer stem cells. In acute myeloid leukemia (AML), ALDH1A1 protects leukemiainitiating cells from a number of antineoplastic agents, and proves vital for the establishment of human AML xenografts in mice. ALDH2, which is located in mitochondria, has a major role in alcohol metabolism by clearing ethanol-derived acetaldehyde. Haematopoietic stem cells require ALDH2 for protection against acetaldehyde, which can cause damage to DNA, leading to insertions, deletions, chromosomal rearrangements, and translocations. Mutations compromise stem cell function, and thereby threaten blood homeostasis. We review here the potential of targeting the enzymatic activity of aldehyde dehydrogenases in acute leukemia.

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“…ALDH-positive (ALDH + ) leukemia cells have greater tumorigenicity and chemotherapy resistance compared to ALDH-negative cells [ 14 , 15 ]. Additionally, high ALDH activity at diagnosis predicts relapse in a subset of AML patients [ 16 ]. Among the 19 ALDH isoforms identified in humans, the most prominent are ALDH1 isoforms (ALDH1A1-3, ALDHB1, and ALDH1L1&2) and the ALDH2 isoform.…”

Section: Introductionmentioning

confidence: 99%

Bone marrow stromal cells induce an ALDH+ stem cell-like phenotype and enhance therapy resistance in AML through a TGF-β-p38-ALDH2 pathway

Yuan

Dana

et al. 2020

PLoS ONE

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The bone marrow microenvironment (BME) in acute myeloid leukemia (AML) consists of various cell types that support the growth of AML cells and protect them from chemotherapy. Mesenchymal stromal cells (MSCs) in the BME have been shown to contribute immensely to leukemogenesis and chemotherapy resistance in AML cells. However, the mechanism of stroma-induced chemotherapy resistance is not known. Here, we hypothesized that stromal cells promote a stem-like phenotype in AML cells, thereby inducing tumorigenecity and therapy resistance. To test our hypothesis, we co-cultured AML cell lines and patient samples with BM-derived MSCs and determined aldehyde dehydrogenase (ALDH) activity and performed gene expression profiling by RNA sequencing. We found that the percentage of ALDH+ cells increased dramatically when AML cells were co-cultured with MSCs. However, among the 19 ALDH isoforms, ALDH2 and ALDH1L2 were the only two that were significantly upregulated in AML cells co-cultured with stromal cells compared to cells cultured alone. Mechanistic studies revealed that the transforming growth factor-β1 (TGF-β1)-regulated gene signature is activated in AML cells co-cultured with MSCs. Knockdown of TGF-β1 in BM-MSCs inhibited stroma-induced ALDH activity and ALDH2 expression in AML cells, whereas treatment with recombinant TGF-β1 induced the ALDH+ phenotype in AML cells. We also found that TGF-β1-induced ALDH2 expression in AML cells is mediated by the non-canonical pathway through the activation of p38. Interestingly, inhibition of ALDH2 with diadzin and CVT-10216 significantly inhibited MSC-induced ALDH activity in AML cells and sensitized them to chemotherapy, even in the presence of MSCs. Collectively, BM stroma induces ALDH2 activity in AML cells through the non-canonical TGF-β pathway. Inhibition of ALDH2 sensitizes AML cells to chemotherapy.

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High aldehyde dehydrogenase activity at diagnosis predicts relapse in patients with t(8;21) acute myeloid leukemia

Cited by 7 publications

References 34 publications

Fabrication of a three-dimensional bone marrow niche-like acute myeloid Leukemia disease model by an automated and controlled process using a robotic multicellular bioprinting system

Fabrication of a three-dimensional bone marrow niche-like acute myeloid Leukemia disease model by an automated and controlled process using a robotic multicellular bioprinting system

Aldehyde Dehydrogenase Enzyme Functions in Acute Leukemia Stem Cells

Bone marrow stromal cells induce an ALDH+ stem cell-like phenotype and enhance therapy resistance in AML through a TGF-β-p38-ALDH2 pathway

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