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Oncogenic osteoblastic lineage determines response to ATRA revealing a cancer cell non-centric therapeutic approach for MDS and AML.

ABSTRACT: 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 regiment with disparate results in AML. In reported clinical trials responsiveness to ATRA correlates with activation of b-catenin/JAG1 in osteoblasts and Notch1 signaling in MDS/AML cells. ATRA inhibits osteoblastic b-catenin activation in patients and leukemic mice and thus suppresses patient MDS/AML cell growth and survival and promotes their differentiation independent of cytogenetics and mutational profile. ATRA also improves disease outcome in mice with no evidence of relapse and a superior safety profile as compared 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 findings provide a mechanistic biomarker for immediate ATRA repurposing in MDS/AML and demonstrate the therapeutic potential of targeting the niche to evade relapse and overcome toxicity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE262907 | GEO | 2025/01/28

REPOSITORIES: GEO

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Project description:Although 80% of AML patients can initially achieve a complete remission, the long-term disease-free survival is only 40% at 6 years with a 10% 5-year survival rate from first relapse. Most patients do not achieve a second remission. Therefore, relapse after initial response to chemotherapy remains a serious clinical challenge requiring new therapeutic strategies. Annual relapse rates have been calculated 40%, 17%, and 2% in years 1-3, respectively. One of the issues hindering the successful treatment of AML patients, and contributing to disease relapse, is leukaemic cell adhesion and retention in the protective niche of the BMME. Here, the leukaemic cells are surrounded by other cell types that promote their survival, by enabling them to evade destruction by both the immune system and intra-vascular therapies, ultimately leading to the emergence of drug resistance. Given the dependence of AML cells on the BMME, a better understanding of the biological interactions between the leukaemic cells and the haematopoietic niche is needed. In addition, the identification and development of therapies to target these adhesive interactions will enable AML cells to be forced out of their BMME protective niche, into the peripheral circulation, where they will be more susceptible to conventional drug regimens. We have developed and optimised a robust, reproducible, in vitro co-culture model of the AML-BMME. Using the optimised model, several adhesion blocking agents were tested to reduce the number of adhered AML cells. Anti-CD44 treatment was established as the most effective in preventing AML adhesion of OCI-AML3, KG1a and primary AML cells. However, even with maximum dose of the most promising blocking agent, some AML cells still adhered. Following this observation, KG1a and OCI-AML3 cells were treated in co-culture and monoculture. Subsequently paired adhered, non-adhered and monoculture cells were isolated and sent for RNA sequencing in order to perform comparative transcriptomic analysis. The results from these experiments helped us identify novel targets from the persistently adhered AML cells in order to more effectively block their adhesion on our model.

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Oncogenic osteoblastic lineage determines response to ATRA revealing a cancer cell non-centric therapeutic approach for MDS and AML.

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