CD97 Is Associated with Poor Overall Survival in Acute Myeloid Leukemia

Introduction: Acute myeloid leukemia (AML) is a heterogeneous, hematologic malignancy characterized by clonal proliferation of myeloid precursors. Overall survival for patients with AML remains dismal (<50% for younger patients and <10% for older patients) due to high relapse rates, necessitating the identification of novel therapeutic targets. CD97 is a glycoprotein belonging to the EGF-TM7 molecule family, a subgroup of adhesion G-protein coupled receptors. CD97 was shown to play a role in cell migration, adhesion and interaction with cell surface proteins and components of the extracellular matrix. In several solid cancers, CD97 association with integrin was shown to regulate invasion, migration, angiogenesis, and poor survival outcome. Even though CD97 is normally expressed on myeloids and leukocytes, there is sparse data related to its expression on myeloid leukemia cells. In this study, we characterized CD97 expression in patients with AML using publically available data sets to determine its association with patient's clinical and molecular characteristics and clinical outcome.

Methods:CD97 mRNA (RNA Seq V2 RSEM) expression and Z-score data was downloaded from TCGA. We generated Kaplan-Meier survival curves to compare overall (OS) and event-free (EFS) survival between patients with CD97 high (Z≥1) and CD97 low (Z<1) expression after stratification by age, cytogenetic status, transplant status and NPM1 mutation status. Association between CD97 expression and patient clinical and molecular characteristics was performed by Mann-Whitney U's non-parametric t-test and Fisher's exact test. STATA 12.0 SE was used to perform a Cox Proportional Hazards Model.

Results: Patients with cytogenetically normal AML (CN-AML) had significantly higher CD97 expression than cytogenetically abnormal AML (CA-AML) (1.31 fold, p=0.023). Patients with high CD97 expression had significantly higher WBC count (median: 56.1 vs 13.1, p=0.004) and % bone marrow blasts (median: 83 vs 71%, p=0.019). CD97 was significantly higher in patients with NPM1 mutation (n=48) compared with patients with NPM1 wild type (n=125) (1.56 fold, p<0.000). CD97 was also significantly higher in patients with FLT3 mutation (ITD and point mutations) (n=49) compared with patients with FLT3 wild type (n=124) (1.4 fold, p=0.0008). Additionally, CD97 was significantly lower in the patients with RUNX1 mutation (n=17) compared with wildtype gene (n=156) (42.1% lower; p=0.0002).

The OS of the CD97 high was significantly shorter than that of the CD97 low patients (median: 7.35 vs. 24.1 months; p=0.0015). Patients with CD97 high expression had significantly shorter EFS than that of CD97 low (median: 5.35 vs. 12 months; p=0.0015). Furthermore, in CN-AML CD97 high patients had shorter OS than CD97 low patients in CN-AML (median: 7.5 vs 20.5 months; p=0.0045; Figure 3B). In multivariate survival analysis, CD97 high expression was associated with shorter OS when adjusted for age, cytogenetic risk and transplant status (HR= 1.96; 95% Cl: 1.19-3.24; p=0.009).

Because CD97 expression was associated with NPM1 mutation in AML, we stratified patients according to NPM1 mutational status and found that in patients with wildtype NPM1, CD97 high expression was associated with significantly shorter OS (Median survival: 6.35 vs 22.3 months; P= 0.0081) and EFS (Median survival: 5.35 vs 13.4 months; P=0.0006). In patients with NPM1 mutation, a similar but not significant association was observed with CD97 high expression and shorter OS (median survival: 7.5 vs 24.1 months; P=0.1) and EFS (median survival: 5.8 vs 11.1 months; P=0.27).

Furthermore, in patients ≥ 60; CD97 high expression was associated with shorter OS compared with CD97 low (median survival 3.3 vs 11 months; p=0.0019) and EFS (Median survival 2.9 vs 9.2 months; p=0.0092). Similar but not significant association was observed in in patients<60 (Median OS: 27.5 vs 53.9; p=0.2) and (Median EFS 8.5 vs 53.9; p=0.2).

Conclusion: Patients with high CD97 expression had shorter OS and EFS. CD97 was higher in CN-AML compared with CA-AML patients. Additionally, high CD97 was also associated with NPM1 mutation. Our findings demonstrate that CD97 expression contributes to the clinical outcome of patients with AML, particularly in older patients. This study provides rationale for further functional and mechanistic studies aiming to understand the role of CD97 in AML.