Our overall goal is to improve therapies for thus far incurable blood cancers (such as myeloid malignancies) by developing early interventions which stop cancer growth during its earliest phases. The past and current research efforts to identify molecular drivers of adult stem cell dysfunction during aging and cancerous transformation have focused on the study of genetic lesions. Much less attention has been diverted to mechanisms protecting the quality and function of macromolecules other than DNA. The cells’ recycling system, autophagy (“self-eating”), plays important roles in the maintenance of healthy cells and tissues. Our preliminary data demonstrate that a highly selective autophagy pathway, chaperone-mediated autophagy (CMA), functions as an essential safeguard mechanism in particularly cancerous blood-forming stem cells (HSCs). To investigate whether CMA also protects “pre-leukemic” HSCs (stem cells with a high propensity to initiate leukemia) from eradication, we will 1) dissect the cellular and molecular consequences of RNAi-mediated CMA impairment on phenotypically identifiable pre-leukemic stem cells using gold standard in vivo and ex vivo assays and 2) characterize the molecular alterations upon CMA impairment. Together, findings from our study could provide rationales for future therapeutic targeting of this pathway in the context of age-associated myeloid malignancies.