Translating insights from normal, neoplastic hematopoiesis and myeloid disease progression into potential clinical applications

Hematopoiesis;leukemia;not listed

Lim, YitingSmall, Donald ;

Johns Hopkins University

关键词: Hematopoiesis;    leukemia;    not listed;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/37983/LIM-DISSERTATION-2014.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

Certain cancers, especially those occurring in the hematopoietic system, can be identified by their cell of origin, and share many similar properties and signaling pathways to their normal counterparts.We use the hematopoietic system to interrogate the relationship between normal and neoplastic transformation.This work aims to better understand the molecular mechanisms of disease transformation in hematologic malignancies and translate basic biology findings into potential clinical applications.To examine how normal hematopoiesis is perturbed, we investigated how low dose-rate radiation affected hematopoietic cells in a whole animal model, and uncover mechanisms to mitigate this adverse effect.Although the effects of acute radiation exposure have been well studied for many years, it is likely that widespread life-threatening radiation incidents will occur in the form of lethal doses delivered at relatively low rates over protracted time periods.We show that damage to hematopoietic progenitors and hematopoietic failure is a consequence of such radiation exposure.In addition, the anti-malaria agent chloroquine can protect these hematopoietic progenitors by activating ATM, a key player in the DNA damage response pathway, thus enhancing overall survival.We provide a mechanistic explanation and potentially viable prophylaxic therapy for protracted low dose-rate radiation induced death.The Hedgehog signaling pathway is highly conserved and important for development.Though its role in normal hematopoiesis is controversial, it does not impact normal adult hematopoiesis.Hedgehog signaling is aberrantly regulated in many cancers, including several hematopoietic malignancies.We found Hedgehog signaling to be upregulated in human secondary leukemias.We hypothesize that Hedgehog signaling plays a role in disease progression and generated a novel transgenic mouse model of myeloid disease progression.Conditional activation of Hedgehog signaling dramatically accelerated disease progression from a chronic myeloproliferative disorder initiated by an activating mutation in the FLT3 tyrosine kinase receptor to rapidly fatal acute myeloid leukemia.Mice harboring both the FLT3-ITD (a commonly found mutation in adult AML) and SmoM2, (a constitutively active form of Smoothened) alleles died rapidly from AML caused by increased myeloid progenitor proliferation.Pharmacologically inhibiting both Hedgehog and FLT3 pathways synergistically reduced leukemic growth and improved overall survival compared to targeting either pathway alone.