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1015 - INHIBITION OF ENDOTHELIAL MTOR DRIVES HEMATOPOIETIC STEM CELL AGING
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Invited Speaker Presentations / Experimental Hematology 2019;76 (Suppl): S23−S40
1015 - INHIBITION OF ENDOTHELIAL MTOR DRIVES HEMATOPOIETIC STEM CELL AGING Jason Butler1,2,3, Pradeep Ramalingam1 1 Center for Discovery and Innovation, Nutley, United States; 2Georgetown University, Nutley, United States; 3 Hackensack Meridian Health, Nutley, United States Aging leads to a decline in hematopoietic stem cell (HSC) function. While some of these age-related changes reflect intrinsic alterations within HSCs, recent findings suggest that signals from the bone marrow (BM) microenvironment, in particular the BM vascular niche, might play a crucial role in regulating HSC aging. To this end, we recently discovered that aging of BM endothelial cells (BMECs) leads to an altered molecular crosstalk between the BMEC niche and HSCs that instructs young HSCs to behave as aged HSCs. Here, we demonstrate that aging leads to a decrease in mTOR signaling within BMECs that underlies the agerelated impairment of their niche activity. In support of this idea, our findings reveal that pharmacological inhibition of mTOR signaling using Rapamycin, a widely regarded rejuvenating agent and clinically utilized immunosuppressant, has deleterious effects on the hematopoietic system, in part due to its adverse impact on endothelium by inhibition of both mTORC1 and mTORC2 signaling. To formally determine whether EC-specific inhibition of mTOR signaling can influence hematopoietic aging, we conditionally deleted mTOR in ECs (mTOR(ECKO)) of young mice and observed that their BMECs and HSCs displayed all the phenotypic and functional attributes of an aged hematopoietic system. Gene expression profiling of HSCs isolated from young mTOR(ECKO) mice revealed that their transcriptome resembled aged HSCs, both at steady state and following transplantation. Notably, during serial transplantations, these aging-like phenotypic and functional HSC alterations are only maintained in an mTOR(ECKO) microenvironment confirming the role of EC-derived instructive signals in governing HSC aging. Furthermore, analysis of mTOR(ECKO) mice revealed a pro-aging factor wherein its genetic deletion led to a preservation of HSC function in aged mice. These studies have begun to lay the framework for the development of therapeutic modalities designed to restore the functional properties of the aged hematopoietic system to youthful levels and improve overall health span.
1016 - EARLY DIAGNOSIS AND PREVENTION OF AML Liran Shlush WIS, Rehovot, Israel Acute myeloid leukemia (AML) is a devastating disease especially among the elderly. Most AML cases present after a chronic latent phase of age-related clonal hematopoiesis (ARCH), yet while the prevalence of ARCH among the elderly is high (∼30%), AML remains a rare event. Recently, we succeeded to predict preAML cases seven years prior to diagnosis with a sensitivity of ∼40% and a specificity of 98.5%. The most accurate early diagnosis was for cases with mutations in the spliceosome. For these patients we have several drugs that might be useful in AML prevention and clinical trials for AML prevention are under preparation. The future of AML prevention will rely on continues improvement in sensitivity and specificity of the careening assays that will take into account not just somatic mutation data. Future studies on AML prevention should focus not only on the intrinsic properties of the preleukemic mutations but also on the differentiation problem and the changes in the bone marrow microenvironment.
Invited Speaker Presentations / Experimental Hematology 2019;76 (Suppl): S23−S40
1015 - INHIBITION OF ENDOTHELIAL MTOR DRIVES HEMATOPOIETIC STEM CELL AGING Jason Butler1,2,3, Pradeep Ramalingam1 1 Center for Discovery and Innovation, Nutley, United States; 2Georgetown University, Nutley, United States; 3 Hackensack Meridian Health, Nutley, United States Aging leads to a decline in hematopoietic stem cell (HSC) function. While some of these age-related changes reflect intrinsic alterations within HSCs, recent findings suggest that signals from the bone marrow (BM) microenvironment, in particular the BM vascular niche, might play a crucial role in regulating HSC aging. To this end, we recently discovered that aging of BM endothelial cells (BMECs) leads to an altered molecular crosstalk between the BMEC niche and HSCs that instructs young HSCs to behave as aged HSCs. Here, we demonstrate that aging leads to a decrease in mTOR signaling within BMECs that underlies the agerelated impairment of their niche activity. In support of this idea, our findings reveal that pharmacological inhibition of mTOR signaling using Rapamycin, a widely regarded rejuvenating agent and clinically utilized immunosuppressant, has deleterious effects on the hematopoietic system, in part due to its adverse impact on endothelium by inhibition of both mTORC1 and mTORC2 signaling. To formally determine whether EC-specific inhibition of mTOR signaling can influence hematopoietic aging, we conditionally deleted mTOR in ECs (mTOR(ECKO)) of young mice and observed that their BMECs and HSCs displayed all the phenotypic and functional attributes of an aged hematopoietic system. Gene expression profiling of HSCs isolated from young mTOR(ECKO) mice revealed that their transcriptome resembled aged HSCs, both at steady state and following transplantation. Notably, during serial transplantations, these aging-like phenotypic and functional HSC alterations are only maintained in an mTOR(ECKO) microenvironment confirming the role of EC-derived instructive signals in governing HSC aging. Furthermore, analysis of mTOR(ECKO) mice revealed a pro-aging factor wherein its genetic deletion led to a preservation of HSC function in aged mice. These studies have begun to lay the framework for the development of therapeutic modalities designed to restore the functional properties of the aged hematopoietic system to youthful levels and improve overall health span.
1016 - EARLY DIAGNOSIS AND PREVENTION OF AML Liran Shlush WIS, Rehovot, Israel Acute myeloid leukemia (AML) is a devastating disease especially among the elderly. Most AML cases present after a chronic latent phase of age-related clonal hematopoiesis (ARCH), yet while the prevalence of ARCH among the elderly is high (∼30%), AML remains a rare event. Recently, we succeeded to predict preAML cases seven years prior to diagnosis with a sensitivity of ∼40% and a specificity of 98.5%. The most accurate early diagnosis was for cases with mutations in the spliceosome. For these patients we have several drugs that might be useful in AML prevention and clinical trials for AML prevention are under preparation. The future of AML prevention will rely on continues improvement in sensitivity and specificity of the careening assays that will take into account not just somatic mutation data. Future studies on AML prevention should focus not only on the intrinsic properties of the preleukemic mutations but also on the differentiation problem and the changes in the bone marrow microenvironment.