SETBP1 sets the stage

In this issue of Blood, Crespiatico et al¹ explore the impact of the timing (founding event vs secondary acquisition) of SETBP1 mutation on the phenotype of myeloid neoplasms. Using a Vav-SETBP1 model, the authors demonstrate that setbp1 mutation has a profound impact on transcriptional programs of differentiating hematopoietic stem cells, skewing them toward granulocytic differentiation, ultimately resulting in a bone marrow phenotype that resembles human primary myelofibrosis (PMF). Interestingly, the authors confirm the presence of SETBP1 mutations as an early event in patients with triple-negative PMF (TN-PMF). The study provides interesting insight into how early mutations may highjack hematopoiesis to drive disease phenotype while at the same time providing a biomarker for TN-PMF.

SETBP1 is a transcription factor that has gained increasing attention in human diseases in recent years.² Initially found to be involved in hematologic malignancies by virtue of fusion to NUP98 in T-cell acute lymphoblastic leukemia³ and ETV6 in acute myeloid leukemia,⁴ the molecule gained notoriety as a putative oncogene when it was found to be mutated in a high proportion of patients with atypical chronic myeloid leukemia.⁵ Since then, mutations involving amino acids in the SKI homologous region (858-871) have been described at variable frequencies in a spectrum of myeloid malignancies, including myelodysplastic syndrome, acute myeloid leukemia, secondary acute myeloid leukemia, and chronic myelomonocytic leukemia.⁶ 

With this context, Crespiatico et al embarked on an ambitious project to establish the early steps in SETBP1-mediated hematologic malignancies. Using a Cre-mediated recombination driven by the Vav1 promoter, the authors developed a mouse model expressing mutant SETBP1^G870S in the entire hematopoietic system. Using single-cell RNA-sequencing data, the authors found marked perturbations in gene expression that overall favored differentiation to the myeloid/monocytic lineage while suppressing gene expression associated with erythroid differentiation. Interestingly, there was also overexpression of Mef2c (myocyte enhancer factor 2C), a transcription factor involved in megakaryocyte differentiation. The net result of these changes was a phenotype that is remarkably similar to the human PMF. The authors then identified SETBP1 mutations in 19.4% of the patients with TN-PMF and identifiable somatic mutations and, using single-cell targeted DNA sequencing, and confirmed SETBP1 to be an early event in the primary patient samples.

The concept of clonal hierarchy has previously been proposed for myelodysplastic/myeloproliferative neoplasms, where early mutations in clonal hematopoiesis genes, such as DNMT3a, TET2, and ASXL1, cooperate with later acquisitions of mutations in NRAS, RUNX1, SRSF2, and IDH2 to contribute to pathogenesis and disease progression of various myeloid malignancies.⁷ Although myeloid skewing is common to both mutations, both the spectrum of mutations as well as the phenotype is different depending on the mutation arising first. What causes these differences? Crespiatico and colleagues focus on expression of genes that are likely directly under transcriptional control of SETBP1. However, it is now well established that pathogenesis of PMF is driven by a dynamic cross talk between the bone marrow niche perturbed by inflammation and the hematopoietic stem cell bearing the founder mutations.^8,9 It is, therefore, tempting to hypothesize that although mutations in genes like DNMT3a and SETBP1 cause myeloid skewing in the hematopoietic differentiation, the 2 mutations may drive a different inflammatory milieu that results in different phenotypes and evolution of malignancies driven by the 2 mutations. Finally, the authors not only confirm SETBP1 mutations as a possible biomarker for TN-PMF,¹⁰ by putting SETBP1 at the center of pathogenesis of TN-PMF, they provide a possible pathway to target in a group of patients who are most likely to benefit from it.

Conflict-of-interest disclosure: The author declares no competing financial interests.