Abstract
We report herein that Sprouty-Related EVH1 Domain-Containing Protein1 (SPRED1) is downregulated and a prognostic biomarker in adult acute myeloid leukemia (AML). We determined mRNA levels of SPRED1 in the bone marrow mononuclear cells from adult patients, including 113 AMLs and 22 acute lymphoblastic leukemias (ALLs), as well as in 37 healthy control subjects. Significantly decreased SPRED1 mRNA expression was found in AML patients comparing to those in ALL patients and healthy controls, which was confirmed by immunocytochemistry analysis of SPRED1 protein and ELISA measurement of serum SPRED1 level. Further analysis demonstrated that SPRED1 expression was significantly higher for most patients at complete remission after induction treatment than at diagnosis. Moreover, SPRED1 expression was significantly downregulated in M2 and M3 types. Non-acute promyelocytic leukemia (non-APL) patients with decreased SPRED1 had significantly lower 2-year progression-free survival and event-free survival rates. In vitro, ectopic overexpression of SPRED1 leads to a decrease of extracellular signal-regulated kinase (ERK) phosphorylation, induction of apoptosis and reduction of proliferation of THP-1 cells. Our findings suggest SPRED1 is not only a predictor of treatment response, but also an independent prognostic factor for non-APL, and targeting Ras- Mitogen-activated protein kinase (MAPK) signaling may be a promising strategy for the treatment of AML with downregulation of SPRED1.
Highlights
The Sprouty-Related EVH1 Domain-Containing Protein1 (SPRED1) gene is located on chromosome 15q14 and encodes SPRED1 protein, a member of the Sprouty-related protein family
The mRNA expression of the SPRED1 gene in the Bone marrow (BM) of these 172 subjects was determined by Quantitative Real-Time PCR (qRT-PCR)
Lower expression of SPRED1 was observed in the acute myeloid leukemia (AML) group in comparison with those in the healthy control group (HC) (p < 0.05) and acute lymphoblastic leukemias (ALLs) groups (p < 0.05)
Summary
The SPRED1 gene is located on chromosome 15q14 and encodes SPRED1 protein, a member of the Sprouty-related protein family. The germline loss-of-function mutations of SPRED1 result in Legius syndrome, an autosomal dominant human disorder characterized by multiple cafe’-au-lait macules, axillary freckling, learning disabilities and macrocephaly [1, 2]; the exact mechanisms of the pathophysiology of SPRED1 are largely unknown. A recent study demonstrates that SPRED1 interacts with neurofibromin [3], a protein encoded by NF1, mutation of which leads to neurofibromatosis type 1 (NF1) syndrome. It has been well-documented that NF1 is a negative regulator of Ras-MAPK signaling, which is deregulated in most cancers [4, 5]. These advances suggest that SPRED1 may regulate cell proliferation, differentiation and survival by suppressing Ras-MAPK signaling [6].
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