Cells of the surrounding bone marrow microenvironment (niche) have emerged as important regulators of myeloid disease development and progression, leading to myeloproliferative neoplasms, myelodysplasia (MDS) or acute myeloid leukemia (AML). This not only highlights the complexity of the disease but may, at least in part, explain the limitations of current malignant cell targeted therapies to prevent relapse and at the same time opens new avenues for therapeutic intervention. To test this hypothesis, we examined here the therapeutic potential of targeting a potent, niche-driven oncogenic pathway, constitutive activation of b-catenin/Jagged1 signaling in osteoblasts. In humans, this pathway is activated in approximately 40% of MDS and AML patients; and also following hypermethylation of its regulators in MDS patients. Its activation levels increase with disease severity, correlate with MDS to AML transformation and with del(5q)-associated myeloid malignancies. In mice, it leads to MDS rapidly progressing to AML. To test its therapeutic potential, we inhibited Jagged1. We generated a chimeric human-mouse neutralizing antibody that efficiently and specifically binds JAG1 (anti-JAG1) and inhibits Notch1-induced signaling. Administration of anti-JAG1 in leukemic mice with activated b-catenin/Jag1 in their osteoblasts rescued anemia, thrombocytopenia, neutrophilia and lymphocytopenia, relieved myeloid differentiation block and eliminated blasts. Body weight increased with time and lethality was abrogated in treated mice. Blood chemistry profiling indicated lack of any toxicity following treatment as indicated by normal liver and kidney function and absence of inflammation, dyslipidemia or pancreatitis. In contrast, chemotherapy at a dose simulating the induction regimen used in patients, dramatically exacerbated anemia, thrombocytopenia and lymphocytopenia without decreasing blasts leading to increased lethality due to bone marrow failure. Emphasizing relevance to human disease, anti-JAG1 treatment of patient-derived samples with activated b-catenin/JAG1 in their osteoblasts, inhibited MDS and AML cell growth and survival and promoted myeloid and erythroid differentiation through its actions on osteoblasts. Responsiveness was observed across patients belonging to diverse disease subtypes and categories including patients with adverse cytogenetics and high-risk groups. Confirming the specificity of anti-JAG1 action, no effect was observed in cells from patients without activated b-catenin/JAG1 in their osteoblasts or healthy subjects and the magnitude of the response correlated with the levels of b-catenin/JAG1 activation in osteoblasts. These results suggest the therapeutic efficacy of blocking JAG1 and its superiority to chemotherapy in osteoblastic, b-catenin-driven MDS/AML that could impact 1/3 of MDS and AML patients. In addition, they suggest that targeting the niche may be an approach to avoid toxicity and overcome MDS/AML cell mutation dependence and clonal resistance that follows standard of care, and therefore, prevent relapse.

Citation Format: Ioanna Mosialou, Abdullah M Ali, Rachel Adams, Adam Corper, Catherine M Woods, Xiaomin Fan, Azra Raza, Stavroula Kousteni. A niche directed therapy for the treatment of myelodysplasia and acute myeloid leukemia [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A25.