HSPA9 was previously identified as a candidate gene in a commonly deleted region (CDR) associated with myelodysplastic syndrome (MDS), a clonal hematopoietic stem cell disorder. Cytogenetic abnormalities occur in ~50% of MDS patients and an interstitial deletion or loss of chromosome 5 containing HSPA9 is the most common, occurring in up to 25% of patients. In order to understand the role of HSPA9 in hematopoiesis and disease development, we created an Hspa9 knockout mouse model. We characterized hematopoiesis of heterozygous mice (Hspa9+/-), which have a 50% reduction in Hspa9 expression, modeling the heterozygous loss of HSPA9 and 50% reduction in mRNA observed in MDS patients. Homozygous knockout of Hspa9 is embryonic lethal prior to fetal liver hematopoiesis, preventing further evaluation of hematopoiesis in Hspa9-/- mice.
Analysis of stem, progenitor and mature stages of hematopoiesis up to 18 months of age identified no significant differences in Hspa9+/- mice compared to Hspa9+/+ littermates in vivo. However, as early as 2 months of age, Hspa9+/- mice have a significant reduction in CFU-PreB colony formation in vitro, indicating a B-cell progenitor defect. This reduction in colony formation is hematopoietic-cell intrinsic and likely due to a functional B-cell progenitor defect, since B-cell progenitor frequencies in Hspa9+/- mice are normal. Gene expression array analysis revealed a reduction in gene expression pathways associated with proliferation and activation of B-lymphocytes. Gene expression analysis of hematopoietic progenitor cells from MDS patients also identified B-cell signaling pathways as the most down-regulated pathways. IL-7 added exogenously to CFU-PreB cultures was able to partially rescue the reduction in Hspa9+/- CFU-PreB colony formation, further indicating dysfunctional IL-7 signaling in Hspa9+/- B-cells.
To explore the contribution of Hspa9 to altered IL-7R signaling, we interrogated an IL-7 dependent cell line treated with an Hspa9 or non-targeting control siRNA. Knockdown of Hspa9 resulted in a significant growth defect in these cells and reduced Stat5 phosphorylation following IL-7 stimulation of cytokine-starved cells. Collectively, these data implicate Hspa9 in IL-7R signaling in B-cells. Further work will determine whether HSPA9 loss contributes to the reduction in B-cell progenitors and increased B-cell apoptosis observed in patients with MDS.
","abstract_html":"<p>HSPA9 was previously identified as a candidate gene in a commonly deleted region (CDR) associated with myelodysplastic syndrome (MDS), a clonal hematopoietic stem cell disorder. Cytogenetic abnormalities occur in ~50% of MDS patients and an interstitial deletion or loss of chromosome 5 containing HSPA9 is the most common, occurring in up to 25% of patients. In order to understand the role of HSPA9 in hematopoiesis and disease development, we created an Hspa9 knockout mouse model. We characterized hematopoiesis of heterozygous mice (Hspa9+/-), which have a 50% reduction in Hspa9 expression, modeling the heterozygous loss of HSPA9 and 50% reduction in mRNA observed in MDS patients. Homozygous knockout of Hspa9 is embryonic lethal prior to fetal liver hematopoiesis, preventing further evaluation of hematopoiesis in Hspa9-/- mice.</p><p>Analysis of stem, progenitor and mature stages of hematopoiesis up to 18 months of age identified no significant differences in Hspa9+/- mice compared to Hspa9+/+ littermates in vivo. However, as early as 2 months of age, Hspa9+/- mice have a significant reduction in CFU-PreB colony formation in vitro, indicating a B-cell progenitor defect. This reduction in colony formation is hematopoietic-cell intrinsic and likely due to a functional B-cell progenitor defect, since B-cell progenitor frequencies in Hspa9+/- mice are normal. Gene expression array analysis revealed a reduction in gene expression pathways associated with proliferation and activation of B-lymphocytes. Gene expression analysis of hematopoietic progenitor cells from MDS patients also identified B-cell signaling pathways as the most down-regulated pathways. IL-7 added exogenously to CFU-PreB cultures was able to partially rescue the reduction in Hspa9+/- CFU-PreB colony formation, further indicating dysfunctional IL-7 signaling in Hspa9+/- B-cells.</p><p>To explore the contribution of Hspa9 to altered IL-7R signaling, we interrogated an IL-7 dependent cell line treated with an Hspa9 or non-targeting control siRNA. Knockdown of Hspa9 resulted in a significant growth defect in these cells and reduced Stat5 phosphorylation following IL-7 stimulation of cytokine-starved cells. Collectively, these data implicate Hspa9 in IL-7R signaling in B-cells. Further work will determine whether HSPA9 loss contributes to the reduction in B-cell progenitors and increased B-cell apoptosis observed in patients with MDS.</p>","abstract_has_math":false,"creators":["Krysiak, Kilannin"],"institution":null,"degree_name":"Doctor of Philosophy (PhD)","degree_level":"Dissertation","degree_discipline":"Biology and Biomedical Sciences: Molecular Genetics and Genomics","degree_department":null,"school":null,"contributors":["Matthew Walter"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2014,"date_issued":"2014-09-01T07:00:00Z","date_published":"2014-09-01T07:00:00Z","updated_at":"2026-07-24T06:12:41Z","subjects":["B-cells","Hematopoiesis","Hspa9","IL-7","Myelodysplastic Syndrome","Stat5"],"languages":["English (en)"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier.doi","label":"DOI","values":["https://doi.org/10.7936/K7BV7DN3"],"render_values":[{"text":"https://doi.org/10.7936/K7BV7DN3","href":"https://doi.org/10.7936/K7BV7DN3","code":true}]}]},"links":{"outbound_url":"https://openscholarship.wustl.edu/etd/1314","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Matthew Walter"]},{"key":"dc:creator","label":"Author","values":["Krysiak, Kilannin"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.available","label":"Dc Date Available","values":["2016-10-07T07:00:00Z"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Biology and Biomedical Sciences: Molecular Genetics and Genomics"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["B-cells","Hematopoiesis","Hspa9","IL-7","Myelodysplastic Syndrome","Stat5"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["English (en)"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://openscholarship.wustl.edu/etd/1314"]},{"key":"dc:identifier.doi","label":"DOI","values":["https://doi.org/10.7936/K7BV7DN3"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["HSPA9 was previously identified as a candidate gene in a commonly deleted region (CDR) associated with myelodysplastic syndrome (MDS), a clonal hematopoietic stem cell disorder. Cytogenetic abnormalities occur in ~50% of MDS patients and an interstitial deletion or loss of chromosome 5 containing HSPA9 is the most common, occurring in up to 25% of patients. In order to understand the role of HSPA9 in hematopoiesis and disease development, we created an Hspa9 knockout mouse model. We characterized hematopoiesis of heterozygous mice (Hspa9+/-), which have a 50% reduction in Hspa9 expression, modeling the heterozygous loss of HSPA9 and 50% reduction in mRNA observed in MDS patients. Homozygous knockout of Hspa9 is embryonic lethal prior to fetal liver hematopoiesis, preventing further evaluation of hematopoiesis in Hspa9-/- mice.
Analysis of stem, progenitor and mature stages of hematopoiesis up to 18 months of age identified no significant differences in Hspa9+/- mice compared to Hspa9+/+ littermates in vivo. However, as early as 2 months of age, Hspa9+/- mice have a significant reduction in CFU-PreB colony formation in vitro, indicating a B-cell progenitor defect. This reduction in colony formation is hematopoietic-cell intrinsic and likely due to a functional B-cell progenitor defect, since B-cell progenitor frequencies in Hspa9+/- mice are normal. Gene expression array analysis revealed a reduction in gene expression pathways associated with proliferation and activation of B-lymphocytes. Gene expression analysis of hematopoietic progenitor cells from MDS patients also identified B-cell signaling pathways as the most down-regulated pathways. IL-7 added exogenously to CFU-PreB cultures was able to partially rescue the reduction in Hspa9+/- CFU-PreB colony formation, further indicating dysfunctional IL-7 signaling in Hspa9+/- B-cells.
To explore the contribution of Hspa9 to altered IL-7R signaling, we interrogated an IL-7 dependent cell line treated with an Hspa9 or non-targeting control siRNA. Knockdown of Hspa9 resulted in a significant growth defect in these cells and reduced Stat5 phosphorylation following IL-7 stimulation of cytokine-starved cells. Collectively, these data implicate Hspa9 in IL-7R signaling in B-cells. Further work will determine whether HSPA9 loss contributes to the reduction in B-cell progenitors and increased B-cell apoptosis observed in patients with MDS.
"]},{"key":"dc:title","label":"Title","values":["The Role of Hspa9 in Mouse Hematopoiesis and IL-7 Receptor Signaling"]}]}],"canonical_facts":{"dc:contributor":["Matthew Walter"],"dc:creator":["Krysiak, Kilannin"],"dc:date.available":["2016-10-07T07:00:00Z"],"dc:description.abstract":["HSPA9 was previously identified as a candidate gene in a commonly deleted region (CDR) associated with myelodysplastic syndrome (MDS), a clonal hematopoietic stem cell disorder. Cytogenetic abnormalities occur in ~50% of MDS patients and an interstitial deletion or loss of chromosome 5 containing HSPA9 is the most common, occurring in up to 25% of patients. In order to understand the role of HSPA9 in hematopoiesis and disease development, we created an Hspa9 knockout mouse model. We characterized hematopoiesis of heterozygous mice (Hspa9+/-), which have a 50% reduction in Hspa9 expression, modeling the heterozygous loss of HSPA9 and 50% reduction in mRNA observed in MDS patients. Homozygous knockout of Hspa9 is embryonic lethal prior to fetal liver hematopoiesis, preventing further evaluation of hematopoiesis in Hspa9-/- mice.
Analysis of stem, progenitor and mature stages of hematopoiesis up to 18 months of age identified no significant differences in Hspa9+/- mice compared to Hspa9+/+ littermates in vivo. However, as early as 2 months of age, Hspa9+/- mice have a significant reduction in CFU-PreB colony formation in vitro, indicating a B-cell progenitor defect. This reduction in colony formation is hematopoietic-cell intrinsic and likely due to a functional B-cell progenitor defect, since B-cell progenitor frequencies in Hspa9+/- mice are normal. Gene expression array analysis revealed a reduction in gene expression pathways associated with proliferation and activation of B-lymphocytes. Gene expression analysis of hematopoietic progenitor cells from MDS patients also identified B-cell signaling pathways as the most down-regulated pathways. IL-7 added exogenously to CFU-PreB cultures was able to partially rescue the reduction in Hspa9+/- CFU-PreB colony formation, further indicating dysfunctional IL-7 signaling in Hspa9+/- B-cells.
To explore the contribution of Hspa9 to altered IL-7R signaling, we interrogated an IL-7 dependent cell line treated with an Hspa9 or non-targeting control siRNA. Knockdown of Hspa9 resulted in a significant growth defect in these cells and reduced Stat5 phosphorylation following IL-7 stimulation of cytokine-starved cells. Collectively, these data implicate Hspa9 in IL-7R signaling in B-cells. Further work will determine whether HSPA9 loss contributes to the reduction in B-cell progenitors and increased B-cell apoptosis observed in patients with MDS.
"],"dc:identifier":["https://openscholarship.wustl.edu/etd/1314"],"dc:identifier.doi":["https://doi.org/10.7936/K7BV7DN3"],"dc:language":["English (en)"],"dc:subject":["B-cells","Hematopoiesis","Hspa9","IL-7","Myelodysplastic Syndrome","Stat5"],"dc:title":["The Role of Hspa9 in Mouse Hematopoiesis and IL-7 Receptor Signaling"],"thesis:degree_discipline":["Biology and Biomedical Sciences: Molecular Genetics and Genomics"],"thesis:degree_level":["Dissertation"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T06:12:41Z"}