Targeting the Osteoblast in Myelodysplasia and Acute Myeloid Leukemia (2015)

Abstract It has previously been shown that an activating mutation in β-catenin in osteoblasts leads to the development of myelodysplasia (MDS) with rapid progression to AML in mice through upregulation of Jagged1 expression in osteoblasts and subsequent activation of Notch signaling in hematopoietic cells. The disease is cell autonomous, because it can be transferred to healthy, lethally irradiated recipients. Moreover, the AML phenotype is associated with clonal evolution at the cytogenetic level since common clonal abnormalities are detected in leukemic blasts from all leukemic mice examined. Revealing the relevance of these observations to human disease, activated β-catenin/Notch signaling was identified in 30% of patients with MDS or AML arising from previous MDS. In the current study we examined the efficacy of a monoclonal mouse anti-human Jagged1 ab (JAG1 ab) as a therapeutic agent for osteoblast-induced MDS/AML. JAG1 ab, which recognizes EGF2/EGF4 domains of human, mouse and rat JAG-1, efficiently bound to them with an EC50 ≤ 0.066 nM (11ng/ml) and dose dependently inhibited Jagged-1 induced Notch signaling with an IC50 ≤ 6nM (1ug/ml) in a Notch reporter assay. Single administration pharmacokinetic (PK) analysis in mice for 3 mg/kg BW showed maximum blood concentration (6.26 µg/ml) in 24 hr, and a terminal half-life of 36 hrs. Organ dysfunction or toxicity was not observed at concentrations as high as 30 mg/kg BW for 5 weeks. The efficacy of weekly subcutaneous administration of 3 mg/kg BW was examined in the AML model of activated β-catenin in osteoblasts (Ctnnb1CAosb mice). Administration of JAG1 ab atpost natal day 8, a time at which MDS/AML has fully developed, prevented anemia, neutrophilia and lymphocytopenia of Ctnnb1CAosb mice. Infiltration of blood with leukemia blasts was reversed within 2 weeks following JAG1 ab administration (2 doses). JAG1 ab reversed the increase in the LSK+/CD150+/CD48- subset of long term repopulating HSC progenitors, the leukemia initiating population in Ctnnb1CAosb mice. The percentage of mature myeloid population (CD11b+/Gr1+) increased in the JAG1 ab treated mice suggesting that blocking Jagged-1 signaling promotes myeloid maturation. Indeed, JAG ab abolished myeloid block as shown by the decrease in the ckit+/CD11b+/Gr1 cells that define immature myeloid progenitors. Dysplastic features seen in the marrow, spleen and liver of Ctnnb1CAosb mice were absent in JAG ab-treated animals and normal trilineage hematopoiesis was established. As a result, JAG1 ab prevented lethality of Ctnnb1CAosb mice and progressively increased body weight for a period of at least 12 weeks, the entire time that the treatment was maintained. Upon termination of the treatments, blast infiltration in the blood appeared within 5 weeks with subsequent development of full blown AML phenotype leading to lethality within 23 weeks. These results suggest that blocking Jagged-1 signaling between osteoblasts and HSCs efficiently treats osteoblast-induced MDS/AML in mice and may have a therapeutic application in patients with MDS and MDS transformed to AML. Disclosures No relevant conflicts of interest to declare.