Transcriptomic Features Associated With Kinase Inhibitor Sensitivity in KMT2A- Rearranged AML

Abstract

Background/Aim: KMT2A-rearranged (KMT2A-r) acute myeloid leukemia (AML) has a transcriptional program, but its relationship to drug sensitivity remains incompletely characterized. This study investigated whether a KMT2A-r-like transcriptomic state is associated with ex vivo kinase inhibitor sensitivity.

Materials and Methods: TARGET-AML RNA-sequencing data with fusion and cytogenetic annotations were used to define a predefined, biology-informed, continuous KMT2A-r identity score based on KMT2A-rearrangement-associated genes. The score was applied to Beat AML primary samples with matched normalized expression, ex vivo drug-response area under the curve (AUC) values, malignant cell-type scores, and FLT3-internal tandem duplication status. Associations were assessed using Spearman correlation and covariate-adjusted linear regression.

Results: KMT2A-r AML exhibited increased expression of HOXA genes, MEIS1, PBX3, MEF2C, and FLT3 in TARGET-AML. The identity score differentiated KMT2A-r AML from other fusion groups in TARGET-AML; when applied to Beat AML, higher KMT2A-r identity scores were associated with lower AUC values for kinase inhibitors. After adjustment for malignant cell-type scores and FLT3-internal tandem duplication status, cabozantinib, sorafenib, and pelitinib retained significant negative associations with AUC. Further adjustment for FLT3 expression attenuated these associations, whereas an FLT3-excluded score preserved their direction.

Conclusion: A KMT2A-r-like transcriptomic state is associated with candidate kinase inhibitor sensitivity patterns in primary AML datasets and appears linked to, but not fully explained by, FLT3-related biology.

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Cite

BibTeX RIS

BibTeX

@article{choi2026transcriptomic,
  title = {{Transcriptomic Features Associated With Kinase Inhibitor Sensitivity in KMT2A- Rearranged AML}},
  author = {WONWOO CHOI and SANGGYU LEE},
  journal = {Cancer Genomics \& Proteomics},
  year = {2026},
  month = oct,
  doi = {10.21873/cgp.20621},
  url = {https://doi.org/10.21873/cgp.20621},
  note = {CC BY-NC-ND 4.0},
}

RIS

TY  - JOUR
TI  - Transcriptomic Features Associated With Kinase Inhibitor Sensitivity in KMT2A- Rearranged AML
AU  - WONWOO CHOI
AU  - SANGGYU LEE
PY  - 2026
DA  - 2026/10/31
JO  - Cancer Genomics & Proteomics
DO  - 10.21873/cgp.20621
UR  - https://doi.org/10.21873/cgp.20621
AB  - Background/Aim: KMT2A-rearranged (KMT2A-r) acute myeloid leukemia (AML) has a transcriptional program, but its relationship to drug sensitivity remains incompletely characterized. This study investigated whether a KMT2A-r-like transcriptomic state is associated with ex vivo kinase inhibitor sensitivity.  Materials and Methods: TARGET-AML RNA-sequencing data with fusion and cytogenetic annotations were used to define a predefined, biology-informed, continuous KMT2A-r identity score based on KMT2A-rearrangement-associated genes. The score was applied to Beat AML primary samples with matched normalized expression, ex vivo drug-response area under the curve (AUC) values, malignant cell-type scores, and FLT3-internal tandem duplication status. Associations were assessed using Spearman correlation and covariate-adjusted linear regression.  Results: KMT2A-r AML exhibited increased expression of HOXA genes, MEIS1, PBX3, MEF2C, and FLT3 in TARGET-AML. The identity score differentiated KMT2A-r AML from other fusion groups in TARGET-AML; when applied to Beat AML, higher KMT2A-r identity scores were associated with lower AUC values for kinase inhibitors. After adjustment for malignant cell-type scores and FLT3-internal tandem duplication status, cabozantinib, sorafenib, and pelitinib retained significant negative associations with AUC. Further adjustment for FLT3 expression attenuated these associations, whereas an FLT3-excluded score preserved their direction.  Conclusion: A KMT2A-r-like transcriptomic state is associated with candidate kinase inhibitor sensitivity patterns in primary AML datasets and appears linked to, but not fully explained by, FLT3-related biology.
SN  - 1109-6535
SN  - 1790-6245
ER  -

Abstract

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