Higher Expression of Suppressor of Cytokine Signaling1 (SOCS1) in the Bone Marrow Is an Unfavorable Prognostic Factor in Adult Patients with De Novo Acute Myeloid Leukemia

Introduction

Suppressor of cytokine signaling1 (SOCS1) protein, which encodes a member of the signal transducers and activators of transcription (STATs)-induced inhibitors, takes part in a negative regulation of cytokine signaling. The mechanism of SOCS1 in tumor carcinogenesis is complex and remains to be defined. Till now, there have been no studies concerning the prognostic implication of SOCS1 expression in acute myeloid leukemia (AML).

Methods and Materials

A total of 223 adult patients with newly diagnosed de novo AML who had enough cryopreserved cells for analysis at the National Taiwan University Hospital were enrolled consecutively. SOCS1 expression in bone marrow (BM) mononuclear cells was analyzed by quantitative real-time polymerase chain reaction. The results were correlated with FAB subtypes, clinical features, cytogenetics, other genetic alterations, and clinical outcome.

Result

The median value of SOCS1 expression was used as the cut-off value to divide patients into lower- and higher-expression groups. Higher SOCS1 expression was closely associated with older age (P=0.032) but inversely related to FAB M1 subtype and t(8;21)(q22;q22). There was no difference in other clinical parameters, including sex, hemoglobin level, white blood cell (WBC) counts, blast counts, and lactate dehydrogenase level between the two groups. Compared to patients with lower SOCS1 expression, those with higher expression had higher incidence of CD7 and CD34 expression on leukemic cells. To investigate the interactions of SOCS1 expression and other genetic alterations in the pathogenesis of AML, a complete mutational screening of 17 genes was performed. Higher SOCS1 expression was closely associated with NPM1 mutation and DNMT3A mutation (33% vs. 14.4%, P=0.002 and 20.9% vs. 10.8%, P=0.044, respectively), but negatively associated with CEBPA mutation (5.4% vs. 18.9%, P=0.002).

Of the 154 AML patients receiving conventional intensive induction chemotherapy, 112 (72.7%) patients achieved complete remission (CR). The patients with higher SOCS1 expression had a lower probability of achieving CR than those with lower SOCS1 expression (62.9% vs. 81%, P=0.001). With a median follow-up time of 37 months (ranges, 0 to 160), patients with higher SOCS1 expression had poorer overall survival (OS) than those with lower SOCS1 expression (median 20 months vs. not reached, P=0.004). The same was also true among the patients with intermediate-risk cytogenetics and normal karyotype. In multivariate analysis, higher SOCS1 expression was an independent poor prognostic factor for OS in total cohort (relative risk, RR 1.947, 95% CI 1.081-3.508, P=0.026) irrespective of age, WBC, cytogenetics, NPM1/FLT3-ITD and CEBPA mutation. In the 77 cytogenetically-normal patients, higher SOCS1 expression was still an independent poor prognostic factor (RR 2.410, 95% CI 1.012-5.738, P=0.047).

Interestingly, a scoring system incorporating SOCS1 expression and six other risk factors, including age, WBC, karyotype, FLT3/ITD, and mutations of NPM1 and CEBPA, into survival analysis was proved to be very useful to stratify AML patients into different risk groups (P =0.002).

Conclusion

AML patients with higher SOCS1 expression had distinct clinic-biologic features and poorer outcome. BM SOCS1 expression may serve as a new biomarker to risk stratify the patients.