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Updated: Jun 26, 2025
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Identification of Key Factors Regulating Self-renewal and Differentiation in EML Hematopoietic Precursor Cells by RNA-sequencing Analysis
Published on: November 11, 2014
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A transcriptomic based deconvolution framework for assessing differentiation stages and drug responses of AML
E Onur Karakaslar1,2,3, Jeppe F Severens1,2,3, Elena Sánchez-López3,4
1Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands.
NPJ Precision Oncology
|May 18, 2024
Summary
This study shows that cell maturation stages in acute myeloid leukemia (AML) predict drug resistance, particularly to Venetoclax. This finding offers a new way to personalize AML treatment based on cell phenotype.
Area of Science:
- Hematology
- Molecular Biology
- Genomics
Background:
- Acute myeloid leukemia (AML) diagnosis increasingly relies on genetic mutations for prognosis and treatment selection.
- However, the maturational arrest of AML blast cells is regaining importance for predicting drug responses.
Purpose of the Study:
- To assess the utility of estimated cell compositions (ECCs) derived from bulk RNA-seq data in reconstituting morphological differentiation stages (FAB) in AML.
- To determine if ECCs can predict ex-vivo drug resistance, specifically to Venetoclax.
- To investigate the relationship between CD14+ monocyte phenotype, BCL-2 protein abundance, and Venetoclax resistance.
Main Methods:
- Deconvolution of 1350 bulk RNA-seq samples from five AML cohorts using a single-cell healthy bone marrow reference.
- Reconstitution of morphological differentiation stages (FAB) using estimated cell compositions (ECCs).
- Validation of ECC-based drug resistance predictions using LUMC proteomics data and correlation with patient survival.
Main Results:
- Morphological differentiation stages (FAB) were accurately reconstituted using ECCs.
- ECCs reliably predicted ex-vivo resistance to Venetoclax, particularly in AML with a CD14+ monocyte phenotype.
- BCL-2 protein abundance showed distinct clustering in NPM1-mutated AML related to CD14+ monocyte percentages, impacting Venetoclax response.
- Venetoclax resistance predictions were extendable to AML subtypes lacking recurrent genetic abnormalities, including MDS-related and secondary AML.
- Patients with CD14+ monocytic dominance treated with Venetoclax/Azacitidine exhibited significantly lower overall survival.
Conclusions:
- A framework for joint modeling of mutation and maturation stages in AML is proposed.
- This framework can guide the testing of new therapeutic agents across diverse AML subtypes.
- Understanding AML cell maturation is crucial for predicting Venetoclax resistance and optimizing treatment strategies.
