Spred1, short for Sprouty-related, EVH1 domain-containing protein 1, is a negative regulator of the RAS-MAPK signaling pathway [5,6,7]. It belongs to the Sprouty related protein family and is crucial for normal cellular growth and development, playing a role in downregulating this key signaling cascade that is involved in numerous biological processes such as cell proliferation, differentiation, and survival [5,6,7]. Genetic models, like knockout (KO) mouse models, have been instrumental in studying its function.

In chronic myelogenous leukemia (CML), Spred1 knockout in SCLtTA/BCR-ABL CML mice, whether global or restricted to hematopoietic cells (HSCs) or endothelial cells (ECs), led to the transformation of chronic phase CML into accelerated phase/blast crisis CML. Spred1 KO increased miR-126 in LSKs, expanding leukemic stem cells likely via hyperactivation of the MAPK/ERK pathway, enhancing Bcl-2-dependent oxidative phosphorylation, and driving the transformation [1]. In melanoma, SPRED1 inactivation in human melanoma cell lines and primary zebrafish melanoma conferred resistance to BRAFV600E inhibition by re-activating MAPK activity, and biallelic deletion was seen in a patient with acquired resistance to MAPK-targeted therapy [2]. In acute myeloid leukemia (AML), in vitro experiments using THP-1 cells showed that demethylation of SPRED1 could inhibit cell proliferation and promote differentiation and apoptosis, possibly through the ERK pathway [3]. Also, in AML, decreased SPRED1 expression was associated with lower 2-year progression-free and event-free survival rates in non-acute promyelocytic leukemia patients, and ectopic overexpression of SPRED1 in THP-1 cells led to decreased ERK phosphorylation, apoptosis induction, and reduced cell proliferation [4].

In summary, Spred1 is essential for regulating the RAS-MAPK signaling pathway, which impacts various biological processes. Model-based research, especially KO mouse models, has revealed its significant roles in diseases such as CML, melanoma, and AML. Understanding Spred1's functions provides insights into disease mechanisms and potential therapeutic targets for these malignancies.