High Expression of ARMCX1 Predicts Poor Survival in Intensively Treated Older Acute Myeloid Leukemia Patients (≥ 60 years)
Authors: Mikesch Jan-Henrik , Sauerland Christina , Herold Tobias , Görlich Dennis , Bormann Eike , Hartmann Wolfgang , Schliemann Christoph , Wörmann Bernhard J , Hiddemann Wolfgang , Spiekermann Karsten , Stelljes Matthias , Krug Utz , Muller-Tidow Carsten , Büchner Thomas , Berdel Wolfgang E , Arteaga Maria Francisca 
Published: October 2019

Abstract
The Armadillo repeat-containing X-linked protein 1 (ARMCX1)gene encodes a member of the ALEX family of proteins and is located on the X chromosome. We found this gene aberrantly expressed in acute myeloid leukemia (AML) cells.
We analyzed ARMCX1 expression in a cohort of 508 AML patients who received intensive chemotherapy within AMLCG clinical trial. Expression levels of ARMCX1 were determined in pretreatment bone marrow or peripheral blood samples by using oligonucleotide microarrays (GSE37642). High transcript levels (dichotomized at the median expression) of ARMCX1 were predictors for inferior overall survival (OS) (p=0.0027, Log-Rank test) and a lower rate of complete remission (CR) (p=0.0017). Older patients (≥ 60 years) showed an elevated incidence of high ARMCX1 expression compared to younger patients (<60 years) (56% vs. 44%, p=0.008, Chi-Squared test). In the subgroup analyses we found that for younger AML patients (<60 years) ARMCX1 expression was not predictive for survival (OS, PFS, EFS) and CR. However, in older patients (≥ 60 years) OS (p=0.002, median survival 11 vs 8 months), event free survival (EFS) (p=0.0006, median 6 vs 2 months) and progression free survival (PFS) (p=0.013, median 10 vs 7 months) were significantly lower among patients with high ARMCX1 expression. CR rate of elderly AML patients with low ARMCX1 expression levels was 60% vs. 41% with high levels (P=0.003). Older AML patients with low ARMCX1 expression had a 5-year OS of 20% (vs. 7% for patients with high expression). Furthermore, prognostic significance of high ARMCX1 expression was confirmed in an independent AML patient cohort of 293 AML patients from the HOVON group (GSE6891). Both, OS (p<0.001) and EFS (p<0.001) were significantly inferior for patients with high ARMCX1expression in this cohort.
Multivariate logistic regression did not show any association between ARMCX1 expression and sex, lactatdehydrogenase (LDH) or leukocyte count (WBC). Interestingly, high expression of ARMCX1 was strongly associated with high United Kingdom Medical Research Council (MRC) risk classification (p<0.0001).
Evaluation of ARMCX1 expression against a clinical multivariate Cox-Regression model (age, gender) showed that dichotomized ARMCX1 added a significant amount of information to the model and was a risk factor for OS (p=0.0020, HR= 1.377 (95%-CI 1.124, 1.686)). Strikingly, including MRC risk classification into the multivariate Cox-Regression model high ARMCX1 expression remained a significant risk factor for OS (p=0.0413, HR=1.243 (95%-CI 1.009, 1.531)).
Taken together, we analyzed ARMCX1 expression levels in a large AML patient cohort. In this study, high ARMCX1 expression levels were identified as a negative prognostic factor for AML patients with respect to survival and remission.

Disclosures
Hiddemann: Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding. Stelljes:Pfizer: Consultancy.