Hematopoietic stem and progenitor cells (HSPC) reside in a specialized niche that regulates their proliferative capacity and their fate. There is increasing evidence for similar roles of marrow niches on controlling the behavior of leukemic cells, however whether normal HSC and leukemic cells reside in or functionally compete for the same marrow niche is unclear. We used the MLL-AF9 murine acute myeloid leukemia in a competitive repopulation model to investigate whether normal HSPC and leukemic cells functionally compete for the same marrow niches. Irradiated recipient mice were transplanted with fixed numbers of MLL-AF9 cells mixed with increasing doses of normal syngeneic whole bone marrow (WBM) or with purified HSPC (LSK). Survival was significantly increased and leukemic progression was delayed proportional to increasing doses of normal WBM or normal LSK cells in multiple independent experiments, with all doses of WBM or LSK cells studied above the threshold for rapid and complete hematopoietic reconstitution in the absence of leukemia. Confocal microscopy demonstrated nests of either leukemic cells or normal hematopoietic cells but not both in the marrow adjacent to endosteum. Early following transplantation, leukemic cells from animals receiving lower LSK doses were cycling more actively than in those receiving higher doses. These results suggest that normal HSPC and AML cells compete for the same functional niche. Manipulation of the niche could impact on response to anti-leukemic therapies, and the numbers of normal HSPC could impact on leukemia outcome, informing approaches to cell dose in the context of stem cell transplantation.
BACKGROUND The ability to distinguish increased platelet destruction from platelet hypo-production is important in the care of patients with bone marrow failure syndromes and patients receiving high dose chemotherapy. The measurement of immature circulating platelets based on RNA content using an automated counter is now feasible. This study evaluated the impact of recent platelet transfusion on measurement of immature platelet parameters. STUDY DESIGN AND METHODS The immature platelet fraction (IPF) and absolute immature platelet number (AIPN) were measured using the Sysmex XE-5000 analyzer prior to and following platelet transfusion in 9 transfusion-dependent patients with marrow failure secondary to aplastic anemia, myelodysplasia or transplantation conditioning. IPF and AIPN were also measured serially over 5 days of storage in 3 plateletpheresis components collected from normal donors. RESULTS Platelet transfusion did not significantly change the mean AIPN in transfused patients. In contrast, IPF decreased significantly from 6.6 ±4.6% at day -1 to 2.3 ±1.4% at day 0 before returning to 4.3 ±2.3% at day +1. In the platelet component, AIPN and IPF% increased significantly over 5 days of storage, most likely due to an artifact of the staining and detection process for stored platelets, no longer detected in vivo once the platelets were transfused. CONCLUSION Platelet transfusion decreases the IPF due to the resultant increase in circulating platelet count. However, platelet transfusion does not change the circulating absolute immature platelet number (AIPN), validating this assay as a reflection of ongoing platelet production by the bone marrow in various clinical settings, regardless of proximity to platelet transfusion.
COVID-19, caused by SARS-CoV-2, is a contagious life-threatening viral disease that has killed more than three million people worldwide to date. Attempts have been made to identify biomarker(s) to stratify disease severity and improve treatment and resource allocation. Patients with SARS-COV-2 infection manifest with a higher inflammatory response and platelet hyperreactivity; this raises the question of the role of thrombopoiesis in COVID-19 infection. Immature platelet fraction (IPF, %) and immature platelet counts (IPC, 910 9 /l) can be used to assess thrombopoiesis. This study investigates whether the level of thrombopoiesis correlates with COVID-19 severity. A large cohort of 678 well-characterized COVID-19 patients was analyzed, including 658 (97%) hospitalized and 139 (21%) admitted to the intensive care unit (ICU). Elevated percentage IPF at presentation was predictive of length of hospitalization (P < 0Á01) and ICU admission (P < 0Á05). Additionally, percentage IPF at the peak was significantly higher among ICU patients than non-ICU patients (6Á9 AE 5Á1 vs 5Á3 AE 8Á4, P < 0Á01) and among deceased patients than recovered patients (7Á9 AE 6Á3 vs 5Á4 AE 7Á8, P < 0Á01). Furthermore, IPC at the peak was significantly higher among ICU patients than non-ICU patients (18Á5 AE 16Á2 vs. 13Á2 AE 8Á3, P < 0Á05) and among patients on a ventilator than those not (22Á1 AE 20Á1 vs.13Á4 AE 8Á4, P < 0Á05). Our study demonstrated that elevated initial and peak values of percentage IPF and IPC might serve as prognostic biomarkers for COVID-19 progression to severe conditions.
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