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One of the standard induction regimens for patients with acute myeloid leukemia (AML) is the ‘7+3’ method, (100–200mg/m2 cytarabine for seven days, 12mg/m2 idarubicin for three days). This treatment regimen achieves up to a 70% complete response (CR) in newly diagnosed de novo AML.1 Chemoresistance of induction therapy is a huge complication in the treatment of AML, with patients who are unable to achieve CR after initial induction therapy having poorer outcomes.
The identification of patients who will fail the standard ‘7+3’ therapy is vital to prepare alternative treatment regimens. Yu-Chiao Chiu, from the Department of Medical Research, Taichung Veterans General Hospital, TX, and colleagues systematically identified resistance functions to examine their interactions in determining chemoresistance.
Gene expressions were profiled using RNA sequencing, and gene set enrichment analysis (GSEA) was used to systematically identify molecular signatures responsible for chemoresistance-related cellular functions. The researchers also combined representative functions to determine whether these cellular functions predicted ‘7+3’ regimen chemoresistance.
The results were combined to develop a prediction model that scores genes to calculate the likelihood of chemoresistance. A value of 0 was set for CR, and 1 for non-CR. Higher scores predicted refractoriness to induction chemotherapy.
The model was validated through the area under the ROC curve (AUROC), and a permutation test was conducted to confirm its significance.
Twenty-eight resistant functions that correlated with the ‘7+3’ regimen were identified. Half of these were also related to mTOR signalling, mitochondrial OXPHOS, myc targets and stem cell activities. Results were validated by comparing expressional differences of the CR group and the non-CR group with a cohort from another study.2
Despite the functions (mTOR, myc, OXPHOS, and stemness) identified all being associated with chemoresistance, the leading-edge component genes of each function were independent. Overall results showed that chemoresistance to the ‘7+3’ regimen is a multifactorial mechanism.
The four-function prediction model predicted ‘7+3’ chemoresistance better than the individual functions. ROC analysis showed the optimal cut-off for each predictor. Higher sensitivity was seen in myc (82%) than mTOR (71%), OXPHOS (41%) and stemness (71%), but myc (77%) had lower specificity than OXPHOS (94%). The Youden3 index indicated that the four-function model better predicted chemoresistance than single pathways.
A seven-gene scoring system was used to predict the achievement of CR through the ‘7+3’ treatment regimen. The score of this system correlated with that of the four-function score, and also predicted CR or non-CR in patients treated with the ‘7+3’ regimen.
Table 1. the seven-gene scoring modelOXPHOS, oxidative phosphorylation
Gene symbol
Gene name
Function category
Weight
CNOT7
CCR4-NOT transcription complex subunit 7
OXPHOS
0.11
DCUN1D4
Defective in cullin neddylation 1 domain containing 4
myc
-0.02
EXOSC2
Exosome component 2
myc
0.11
FKBP4
FKBP prolyl isomerase 4
myc
0.05
NDUFA8
NADH: ubiquinone oxidoreductase subunit A8
OXPHOS
0.10
PRDX4
Peroxiredoxin 4
myc
0.05
RPS27A
Ribosomal protein S27a
mTOR
0.28
The researchers found that the mTOR, myc, OXPHOS, and stemness pathways were all associated with chemoresistance of patients with de novo AML to the ‘7+3’ induction regimen.
Limitations for this study included the small number of patients involved, and as such an independent validation cohort to verify the seven-gene scoring model could not be provided. Other studies were used to reduce this limitation, however prospective studies, analyzing a larger number of patients, are required to validate both the seven-gene scoring model and the four-function model.
References