PROJECT SUMMARY/ABSTRACTJuvenile myelomonocytic leukemia (JMML) is the most common myeloproliferative neoplasm (MPN) inchildhood, and tends to occur in very young children less than 4 years of age. JMML is traditionallycharacterized as being Ras-driven due to mutations in NF1, CBL, KRAS, NRAS, or PTPN11. Traditionalcytotoxic chemotherapeutic agents are ineffective in JMML, and the only curative modality is allogeneichematopoietic stem cell transplantation. Unlike other MPNs, JMML rarely progresses to blast crisis; rather,mortality is due to extramedullary tumor cell expansion leading to organ failure, respiratory failure, bleeding, orinfection. Notably, following allogeneic stem cell transplant, 50% of children succumb to leukemia relapse.This relapse rate in JMML is substantially higher than that of individuals who receive allogeneic stem celltransplant for chronic myelogenous leukemia (CML) in chronic phase (approximately 7% leukemia relapse),implicating a strong hematopoietic stem cell (HSC)-independent component of JMML development andprogression.We envision two distinct mechanisms that potentially account for a HSC-independent means of JMML relapseafter allogeneic HSC transplant. First, the JMML-initiating malignant cells may emerge during embryonicdevelopment prior to and independently from HSCs, and persist postnatally as self-replenishing malignanttissue macrophages. Alternatively, regardless of the origin of the JMML cells, the hyperinflammatory nature ofJMML may damage the bone marrow microenvironment, prohibiting the expansion of normal donor cellsfollowing transplant, permitting residual leukemia cells to outcompete the normal graft, and leading to leukemiarelapse.To address these possibilities, we will use the tamoxifen-inducible Cre recombinase system, which will permityolk sac-restricted expression of the common JMML mutation, Shp2D61Y, to determine if yolk sac-restrictedoncogene expression is sufficient for the post-natal development of MPN. Further, we will examine if inhibitionof the pro-inflammatory protein, PI3K p110?, improves homing, engraftment, expansion, and myeloiddifferentiation of WT donor cells into diseased, Shp2D61Y-expressing recipients.
|Effective start/end date||7/1/16 → 6/30/18|
- National Institutes of Health: $169,650.00