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A niche driven mechanism determines response and a mutation-independent therapeutic approach for myeloid malignancies [mouse]

ABSTRACT: Myeloid cancers such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) remain resistant to standard of care (SOC) and targeted therapies. Here, we identify an oncogenic signal from the niche as a mechanism determining response to all trans-retinoic acid (ATRA), a regimen with disparate results in AML. In samples from clinical trials, responsiveness to ATRA correlates with activation of b-catenin/JAG1 in osteoblastic lineage cells and Notch1 signaling in MDS/AML cells of patients. ATRA inhibits b-catenin activation in patients and leukemic mice. As a result, it specifically suppresses growth and survival and promotes differentiation of MDS/AML cells solely from patients with active b-catenin/JAG1 signaling. This event is independent of cytogenetics and mutational profile. ATRA also improves disease outcome in mice with no evidence of relapse and a superior safety profile to SOC. A circulating skeletal stem cell population expressing activated b-catenin allows patient stratification and monitoring treatment response. A human blocking antibody against JAG1 further improves efficacy, curing mice from leukemia and maintaining the beneficial effects on patient-derived MDS/AML cells. These results demonstrate a niche-directed therapeutic approach, tailored to at least 1/3 of MDS/AML patients that can evade relapse and overcome SOC toxicity, highlighting the therapeutic potential of targeting the niche. b-catenin activation provides an explanation for the differential response to ATRA and a mechanistic biomarker for immediate ATRA repurposing in myeloid malignancies, potentially extending in a broad range of cancers.

ORGANISM(S): Mus musculus

PROVIDER: GSE277597 | GEO | 2025/01/28

REPOSITORIES: GEO

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Project description:Full Title: Multilineage Dysplasia (MLD) in AML correlates with MDS-related cytogenetic abnormalities and a prior history of MDS or MDS/MPN but has no independent prognostic relevance: A comparison of 408 cases classified as “AML not otherwise specified” or “AML with myelodysplasia-related changes” The WHO classification of acute myeloid leukemia (AML) is hierarchically structured and integrates genetic information, data on patients’ history, and multilineage dysplasia (MLD). The category “AML with MDS-related changes” (AML-MRC) is separated from AML not otherwise specified (AML-NOS) by the presence of either MLD, MDS-related cytogenetics or MDS history. To clarify whether MLD alone is clinically relevant, we analyzed 408 adult patients categorized as AML-MRC or AML-NOS. EFS (Median 13.8 months vs. 16.0 months) and 3-year-OS (45.8% vs. 53.9%) did not differ significantly between patients with MLD and without. However, MLD correlated with pre-existing MDS (p<0.001) and MDS-related cytogenetics (p=0.035). Patients with MLD as sole AML-MRC criterion (AML-MLD-sole; n=90) had less frequently FLT3-ITD (p=0.032), and a lower median age than AML-NOS (n=232), but EFS, OS, and WBC did not differ significantly. Contrarily, patients with AML-NOS plus AML-MLD-sole (n=323) versus patients with MDS history or MDS-related cytogenetics (n=85) had better EFS (16.9 vs. 10.7 months; p=0.005) and 3-year-OS (55.8% vs. 32.5%; p=0.001). Gene expression profiles were measured for a subset of 96 patients. Analysis of the expression data showed distinct clusters for AML-MLD-sole and AML-NOS versus AML with MDS-related cytogenetics or MDS history. Thus, MLD demonstrated no independent clinical impact, while cytogenetics and MDS history were of prognostic relevance. This data suggest modifications in a revised WHO proposal. All 96 bone marrow samples were obtained from untreated patients at the time of diagnosis. Cells used for microarray analysis were collected from the purified fraction of mononuclear cells after Ficoll density centrifugation.

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A niche driven mechanism determines response and a mutation-independent therapeutic approach for myeloid malignancies [mouse]

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