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Principal Investigator: Kay Lynn Medina
Organization: MAYO CLINIC ROCHESTER
Fiscal Year: 2023
Award: $318,000
Funding agency: National Institute on Aging
PROJECT SUMMARY
Steady-state hematopoiesis in bone marrow is critical for maintenance of blood cell genesis and immune
competence throughout life. Concomitant with aging, the bone marrow hematopoietic stem cell (HSC)
compartment undergoes cell intrinsic and extrinsic changes that biases hematopoietic output toward the
myeloid lineage. The bias in HSC-subset predominance and change in hematopoietic output contributes to
immune dysfunction in the elderly including an increased propensity to infection and lessened vaccine
responses. Thus, studies focused on understanding essential regulators that support a non-biased, balanced
HSC pool that supports lymphoid differentiation capability has the potential to provide novel therapeutic
avenues to rejuvenate HSC developmental trajectories to restore immune function in the aged. The homeobox
transcription factor Hoxa9 is expressed in primitive HSCs and is inactivated upon lineage commitment. Mice
with germline deletion of hoxa9 are viable but display multilineage deficiencies that are transplantable,
confirming a cell intrinsic defect. Competitive transplantation experiments revealed impaired long-term
repopulating ability and in vitro studies showed poor proliferative responses to early-acting cytokines. In bone
marrow, hoxa9-/- mice exhibit reduced cellularity, impaired lymphoid priming, reductions in lympho-myeloid
progenitors, common lymphoid progenitors, and B cell precursors. Hoxa9-/- mice also have smaller thymi, and
reductions in early thymic progenitors. Interestingly, flow cytometric analysis of the long-term repopulating stem
cell compartment (LT-HSC) in young adult hoxa9-/- mice revealed increased frequencies of LT-HSCs
expressing high levels of the CD150, which is functionally associated with myeloid skewing. This is contrasted
by significant decreases in frequencies of CD150lo LT-HSC in hoxa9-/- marrow, which have balanced lympho-
myeloid potential. Increased numbers of myeloid-biased HSCs along with diminished lymphopoiesis is
reminiscent of aging. A Hoxa9 target gene implicated in age-associated alterations in lymphopoiesis and B cell
genesis in the marrow is p16ink4a. The cyclin dependent kinase inhibitor p16ink4a is virtually undetectable in
HSC and B cell precursors from young mice but increases in both subsets with age. Realtime PCR of Lin-
Sca1+ hematopoietic progenitors from young hoxa9-/- mice revealed increased mRNA transcripts for
p16ink4a. To determine if over expression of p16ink4a was the molecular basis of the lymphoid/B cell
deficiency in hoxa9-/- mice, we generated hoxa9-/-p16ink4a-/- mice. Importantly, deletion of p16ink4a restored
bone marrow and thymus cellularity and rescued the deficiencies in lymphoid, B and T cell precursors in
hoxa9-/- mice. These novel experimental findings support the hypothesis that Hoxa9 suppression of p16ink4a
is critical for lymphopoiesis. At present, there is a paucity of information regarding the role of Hoxa9 in
regulation of lympho-hematopoiesis. The studies detailed in this proposal are aimed at filling this gap in the
knowledge.
Terms: <Age><Aging><Anti-Oncogenes><Antioncogenes><Attention><B blood cells><B cell><B cells><B-Cell Deficiency><B-Cells><B-Lymphocytes><B-cell><Basal Transcription Factor><Basal transcription factor genes><Blood Cells><Blood Precursor Cell><Bone Marrow><Bone Marrow Reticuloendothelial System><CD150><CD150 antigen><CDK Inhibitor Protein><CDK4I><CDKI Protein><CDKN2><CDKN2 Genes><CDKN2A><CDKN2A gene><CDw150 protein><CMM2><Cancer Suppressor Genes><Cell Body><Cell Compartmentation><Cell Compartmentations><Cell Lineage><Cells><Cellular Immune Function><Cellularity><Common Lymphoid Progenitor><Cyclin Kinase Inhibitor><Cyclin-Dependent Kinase Inhibitor><Cyclin-Dependent Kinase Inhibitor 2A Gene><Data><Defect><Development><Elderly><Emerogenes><Exhibits><Frequencies><General Transcription Factor Gene><General Transcription Factors><Genes><Goals><HOXA9 protein><HSC subsets><Hematology><Hematopoiesis><Hematopoietic><Hematopoietic Cellular Control Mechanisms><Hematopoietic Progenitor Cells><Hematopoietic Stem Cell subsets><Hematopoietic stem cells><Homeo Boxes><Homeobox><Homeobox Protein 1G><Homeobox Protein A9><Homeobox Protein HOXA9><Homeodomain Protein HOXA9><INK4><INK4A><Immune Diseases><Immune Disorders><Immune Dysfunction><Immune System Diseases><Immune System Disorder><Immune System Dysfunction><Immune System and Related Disorders><Immunocompetence><Immunodeficiency and Immunosuppression Disorders><Immunologic Competence><Immunologic Diseases><Immunological Competence><Immunological Diseases><Immunological Dysfunction><Immunological System Dysfunction><Impairment><In Vitro><Infection><KO mice><Knock-out Mice><Knockout Mice><Knowledge><Life><Lymphatic cell><Lymphocyte><Lymphocytic><Lymphoid><Lymphoid Cell><Lymphopoiesis><MTS1><MTS1 Genes><Maintenance><Marrow><Messenger RNA><Mice><Mice Mammals><Modeling><Molecular><Murine><Mus><Myelogenous><Myeloid><Null Mouse><Onco-Suppressor Genes><Oncogenes-Tumor Suppressors><Oncogenesis><Output><Peripheral Blood Cell><Progenitor Cells><Proliferating><Publications><Radiation Chimera><Recessive Oncogenes><Regulation><Rejuvenation><Role><SLAM protein><Scientific Publication><T-Cells><T-Lymphocyte><TP16><TSG9A><Thymus><Thymus Gland><Thymus Proper><Thymus Reticuloendothelial System><Time><Transcript><Transcription Factor Proto-Oncogene><Transcription factor genes><Transplantation><Tumor Suppressing Genes><Tumor Suppressor Genes><adult youth><advanced age><aged><ages><blood cell formation><blood stem cell><cytokine><developmental><elders><experiment><experimental research><experimental study><experiments><gene locus><genetic locus><genomic location><genomic locus><geriatric><hematopoietic progenitor><hematopoietic stem progenitor cell><hemopoietic><hemopoietic progenitor><hemopoietic stem cell><hoxa-9 gene product><hoxa9 gene product><humoral immunity deficiency><immune function><late life><later life><lymph cell><lymphocytopoiesis><mRNA><mouse ARF tumor suppressor><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><older adult><older person><oncosuppressor gene><overexpress><overexpression><p14ARF><p16 Genes><p16INK4 Genes><p16INK4A Genes><p16INK4a><p19ARF><progenitor><promoter><promotor><response><senescence><senescent><senior citizen><signaling lymphocytic activation molecule><signaling lympocyte activation molecule><social role><stem cell biology><stem cells><thymus derived lymphocyte><transcription factor><transplant><tumorigenesis><vaccine response><vaccine responsiveness><vaccine-induced response><virtual><young adult><young adulthood>