Pre-clinical Studies of Therapy for Myelodysplastic Syndrome

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

We have modified a previously established in vivo model of myelodysplastic neoplasm (MDS) to now generate mice that have both wild type (WT) and NHD13 (MDS-derived) hematopoiesis by co-transplantation of WT and NHD13 hematopoietic stem cells into WT recipients. We have refined this model to enable transplant of NHD13 MDS hematopoietic cells without using ionizing radiation as a conditioning agent. We have successfully engrafted WT mice with NHD13 BM by pre-treating recipient mice with the Cdc42 inhibitor CASIN, which leads to egress of the WT hematopoietic stem cells. These chimeric mice are used to assess the pre-clinical efficacy of several compounds. In collaboration with Drs. Difilipantonio and Doroshow, and colleagues, we treated chimeric NHD13/WT mice with both FDA-approved and novel DNA methyltransferase inhibitors (DNMTi), to assess efficacy in treatment of MDS. A manuscript characterizing the unanticipated finding that FDA approved DNMTi (5-azacytidine and decitabine) could be both leukemogenic and mutagenic was published in FY2025 (PMID: 40681875). A second manuscript describing the leukemogenic and mutagenic properties and mechanisms of a novel DNMT1 inhibitors (Aza-TdCyd or ATC) is now in press. We have begun a CRADA project with Syntrix to study the effects of a CXCR1/2 inhibitor in NHD13 mice. In addition to the experiments outlined above, we have transferred NHD13 mice to colleagues at more than 15 academic institutions, and have licensed NHD13 mice to industry for pre-clinical studies. These colleagues have treated NHD13 mice with a variety of agents, including kinase inhibitors, histone deacetylase inhibitors, apoptosis inhibitors, and angiogenesis inhibitors. One of these compounds (ACE-536 or luspatercept) recently received FDA approved for treatment of MDS. In collaboration with Dr. Andre Nussenzweig, we have also assessed the mechanisms leading to toxicity of cytarabine, an FDA approved therapy for MDS and acute myeloid leukemia (AML); an article describing these findings was published in FY2025 (PMID: 40562930). In collaboration with Drs. Pavletic and McGraw, we published an overview of MDS biology and therapy in FY2025 (PMID: 39674608), and in a multi-institutional collaboration, we published an overview of drug development for MDS in FY2025 (PMID: 39786387).