SOCS2 is part of a highly prognostic 4-gene signature in AML and promotes disease aggressiveness

Abstract

Acute myeloid leukemia (AML) is a heterogeneous disease with respect to its genetic and molecular basis and to patients´ outcome. Clinical, cytogenetic, and mutational data are used to classify patients into risk groups with different survival, however, within-group heterogeneity is still an issue. Here, we used a robust likelihood-based survival modeling approach and publicly available gene expression data to identify a minimal number of genes whose combined expression values were prognostic of overall survival. The resulting gene expression signature (4-GES) consisted of 4 genes ( SOCS2 , IL2RA , NPDC1 , PHGDH ), predicted patient survival as an independent prognostic parameter in several cohorts of AML patients (total, 1272 patients), and further refined prognostication based on the European Leukemia Net classification. An oncogenic role of the top scoring gene in this signature, SOCS2 , was investigated using MLL-AF9 and Flt3 -ITD/ NPM1c driven mouse models of AML. SOCS2 promoted leukemogenesis as well as the abundance, quiescence, and activity of AML stem cells. Overall, the 4-GES represents a highly discriminating prognostic parameter in AML, whose clinical applicability is greatly enhanced by its small number of genes. The newly established role of SOCS2 in leukemia aggressiveness and stemness raises the possibility that the signature might even be exploitable therapeutically.

<p>Long Noncoding RNA SOCS2-AS Promotes Leukemogenesis in FLT3-ITD+ Acute Myeloid Leukemia Through miRNA-221</p>

“…19 The expression of suppressor of cytokine signaling 2 (SOCS2), one of lncRNAs, would promote leukemogenesis and AML aggressiveness. 11 Moreover, it's reported that SOCS2 can inhibit the carcinogenesis of multiple cancers, such as hepatoma carcinoma, lung cancer, breast carcinoma, and prostate cancer. 20 In this study, we explore the role of SOCS2-AS in FLT3-ITD+ patients.…”

“…10 Suppressor of cytokine signaling-2, as one of LncRNAs, was demonstrated that it is related to AML progression. 11 Laszlo et al reported that higher SOCS2 expression would have a poor outcome in pediatric acute myeloid leukemia. 12 Therefore, exploring the role of SOCS2 in AML will contribute to reveal the molecular mechanism, and provide therapeutic targets for AML treatment.…”

All-trans retinoic acid enhances, and a pan-RAR antagonist counteracts, the stem cell promoting activity of EVI1 in acute myeloid leukemia

“…HSC enriched Lin − Sca-1 + c-Kit + (LSK) cells and common myeloid progenitors (CMPs; Lin − Sca-1 − c-Kit + CD34 + CD16/CD32 low cells; Supplementary Fig. S1A) were isolated from bone marrow (BM) of 6–8 week old C57BL/6 mice (Department of Laboratory Animal Science & Genetics, Himberg, Austria), transduced with pMSCV_MA9_IRES_Venus, and transplanted into sub-lethally irradiated congenic recipient mice 4,32 . Venus + BM or spleen cells from terminally ill mice were considered leukemic cells (LCs), and are referred to as LC LSK_MA9 and LC CMP_MA9 , respectively.…”

Quantitative and molecular differences distinguish adult human medullary and extramedullary haematopoietic stem and progenitor cell landscapes

“…Analysis of highly expressed marker genes for each cluster identified that the clusters at the head of the fork (clusters 3,10,19,14,0,17,6,15,1 and 5) are marked by stem cellassociated genes such as SOCS2, MLLT3 and HOPX (Calvanese et al, 2019;Nguyen et al, 2019;Vitali et al, 2015;Zhou et al, 2015) ( Figure 1D, Table S4). Clusters within the three branches could be attributed to the main haematopoietic lineages.…”