NEW YORK – New research suggests that treatments targeting an inflammation-related pathway containing CD74, JAK1/2, and mTOR can help assuage processes involved in an autosomal dominant preleukemic condition known as familial platelet disorder (FPD), which involves germline mutations in the RUNX1 transcription factor-coding gene.
"RUNX1-FPD is characterized by lifelong mild to moderate thrombocytopenia, platelet dysfunction, and an increased risk of developing hematological malignancies, primarily myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML)," Oregon Health and Science University researcher Anupriya Agarwal, the senior and corresponding author of a study published in Science Translational Medicine on Wednesday, and her colleagues explained, noting that "RUNX1 mutations are also prevalent in patients with AML."
To explore the preleukemic processes associated with RUNX1-FPD, as well as factors influencing progression to MDS or AML, the team used single-cell RNA sequencing. Specifically, they assessed transcriptomic profiles in 122,021 individual bone marrow cells from 10 individuals with RUNX1-FPD and 48,781 scRNA-seq profiles in samples from four unaffected controls, uncovering 18 scRNA-seq-based transcriptome clusters.
Using bone marrow and peripheral blood samples from up to 75 RUNX1-FPD patients and 30 unaffected controls, meanwhile, the researchers also performed a series of in vitro functional assays, cytokine analyses, and digital spatial profiling experiments to characterize functional features contributing to inflammation and other FPD-related phenotypes in bone marrow or in hematopoietic stem and progenitor cells (HSPCs) isolated from it.
Together, the team's analyses highlighted immune cell shifts associated with FPD — from dialed-down B-cell and megakaryocyte-erythroid progenitor cell populations to increased T-cell populations and cytokine activity.
In particular, the team focused on an uptick in gene and protein expression for the inflammatory antigen presentation and macrophage migration inhibitory factor (MIF) receptor CD74 in preleukemia RUNX1-FPD bone marrow samples, along with increased activity of a CD74-mediated pathway in HSPCs from individuals with RUNX1-FPD.
"[W]e identified CD74 as a major driver of inflammatory and pro-survival pathways that contribute to defective hematopoiesis in RUNX1 mutant cells," the authors reported. "Our data suggest that targeting these pathways may ameliorate the hematopoietic dysfunction in patients with RUNX1-FPD and potentially reduce leukemic risk."
Indeed, the investigators detected a dip in RUNX1-FPD-related differentiation and inflammation features when they used genetic or pharmacological approaches, including the macrophage MIF-targeting small molecule ISO-1, to mute CD74 activity in vitro or in mouse models.
Similarly, the team saw diminished FPD phenotypes following treatment with inhibitors targeting mTOR/PI3K and JAK/STAT components downstream of CD74. On the other hand, sensitivity to such inhibitors appeared to be specific to AML cells with higher-than-usual expression of CD74 — a feature found in RUNX1-mutated forms of the blood cancer.
"Approximately 18,000 patients in the USA are estimated to have FPD and are at risk of progressing to leukemia, but currently, there are no available treatments," the authors wrote. "The identification of prevention strategies and early cancer interception has the potential to improve the long-term quality of life and survival of patients with RUNX1-FPD."