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May 21, 2021 by Brittany Enzmann, PhD 2 min read

Publication Highlight: Genotype-phenotype Discordance in AML

Demaree B., et al. Joint profiling of DNA and proteins in single cells to dissect genotype-phenotype associations in leukemia. Nat Commun. 2021 Mar 11;12(1):1583. doi: 10.1038/s41467-021-21810-3. 

Like all cancers, acute myeloid leukemia (AML) is a highly heterogeneous disease. Tumors are often composed of cells with different combinations of mutations and genetic alterations. They are also phenotypically diverse, with cells varying in cell-surface marker signatures, or immunophenotype. In this paper, Demaree et al. investigate the relationship between cellular genotype and immunophenotype in AML patients under different clinical contexts.

What is the relationship between genotype and immunophenotype in leukemic cells?

This study used Mission Bio’s Tapestri Platform to perform high-throughput single-cell proteogenomic profiling (DAb-seq) —a technique that simultaneously measures genotype and immunophenotype from thousands of individual cells —to precisely characterize tumor heterogeneity in three AML patients across multiple treatment time points. 

Main Results:
The authors report that the genotype-immunophenotype dynamics varied across patients under different clinical scenarios. Although the genotype and immunophenotype were tightly correlated in one case, they were decoupled in others. For instance, in one patient blasts with distinct genotypes shared a common immunophenotype. The opposite was true in another patient, where the FLT3 inhibitor gilteritinib, caused cells with similar genotypes to differentiate into various myeloid compartments (each having different immunophenotypes). This illustrates the complex genotype-immunophenotype relationships of AML and underscores the fact that one parameter cannot always be inferred from the other.

Conventionally, DNA sequencing and flow cytometry are used to assess genotype and immunophenotype in separate assays. The study demonstrates that genotype does not always predict immunophenotype in AML clones, underscoring the need to measure these parameters simultaneously in the same cells. Such multimodal analysis in single cells can be utilized to assess therapeutic responses to AML with high specificity hold significant promise for advancing treatment strategies for leukemia and other cancers.

Check out the paper here!

See the co-author, Catherine Smith, MD, discuss this paper in this webinar.

About the Author

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