General AML,   FLT3,  NPM1,  DNMT3A

The prognostic significance of SOCS1 in AML – a Taiwan study

Suppressor of Cytokine Signaling proteins are negative regulators of the JAK/STAT signaling pathway. The clinical implications of Suppressor of Cytokine Signaling 1 (SOCS1) expression in Acute Myeloid Leukemia (AML) is not well understood.

Hsin-An Hou and colleagues from the National Taiwan University Hospital (NTUH), investigated the prognostic significance of SOCS1 expression in the Bone Marrow (BM) of AML patients.  The results of the study were reported in an article published in Blood Cancer Journal on 28th July 2017.

BM samples from 223 de novo AML patients who were treated at NUTH from May 1995 to December 2007 were analyzed for SOCS1 expression using quantitative real-time polymerase chain reaction. Using the median value of BM SOCS1 expression as cut-off, patients were divided into two groups including higher SOCS1 expression (n = 112) and lower SOCS1 expression (n = 111).

The key results of the study were:
  • Compared to patients with lower SOC1 expression, higher SOCS1 expression was closely associated with mutations in NPM1 (33% vs 14.4%, P = 0.002), DNMT3A (22.3% vs 10.8%, P = 0.0029) and FLT3-ITD (30.4% vs 19.8%, P = 0.089) in patients
  • Higher SOCS1 expression inversely correlated with mutations in CEBPA in patients compared to lower SOCS1 expression; 1.5% vs 14.4%, P = 0.001
  • Complete Remission (CR) rate in patients with lower and higher SOCS1 expression; 82.9% vs 62.9%, P = 0.006
  • Median Overall Survival (OS) in patients with lower and higher SOCS1 expression; not reached vs 20 months, P = 0 .003

The authors noted that their study is the first to “demonstrate higher expression of BM SOCS1 is an independent prognostic factor for OS in AML patients”.

Hou et al., concluded by suggesting that higher SOCS1 expression may serve as a new biomarker that would be used in predicting clinical outcomes in AML patients. They further proposed that the use of “SOCS1 targeted therapy may represent a potential new approach for AML patients with higher SOCS1 expression”.

Abstract

Suppressor of cytokine signaling 1 (SOCS1) protein, which encodes a member of signal transducers and activators of transcription-induced inhibitors, takes part in a negative regulation of cytokine signaling. The mechanism of SOCS1 in tumor carcinogenesis is complex and there have been no studies concerning the clinic-biologic implication of SOCS1 expression in acute myeloid leukemia (AML). Here, we first identified that higher bone marrow (BM) SOCS1 expression was closely associated with older age, FLT3-ITD, NPM1 and DNMT3A mutations, but negatively correlated with CEBPA mutation in patients with de novo AML. Compared to patients with lower SOCS1 expression, those with higher expression had lower complete remission rates and shorter overall survival. Further, higher expression of SOCS1 in the BM was an independent unfavorable prognostic factor irrespective of age, white blood cell, cytogenetics and gene mutations. Next, we generated zebrafish model overexpressing SOCS1 by spi1 promoter, which showed kidney marrow from adult SOCS1 zebrafish had increased myelopoiesis, myeloid progenitors and the kidney or spleen structure were effaced and distorted, mimicking leukemia phenotype. The SOCS1/FLT3-ITD double transgenic fish could further facilitate the leukemic process. The results indicate SOCS1 plays an important role in AML and its higher expression serves as a new biomarker to risk-stratify AML patients.

References
  1. Hou H.A. et al. Clinico-biological significance of suppressor of cytokine signaling 1 expression in acute myeloid leukemia. Blood Cancer J. 2017 Jul 28; 7(7): e588. DOI: 10.1038/bcj.2017.67.