Key Points: Using AML as a model, we investigated the effect of treatment and disease evolution on functionally defined cancer stem cell populations. We demonstrate large-scale changes in LSC frequency and phenotype after relapse, best described using high-dimensional space analyses.

Stem cell homing is a multistep endogenous physiologic process that is also used by exogenously administered hematopoietic stem and progenitor cells (HSPCs). This multistep process involves cell migration and is essential for hematopoietic stem cell transplantation. The process can be manipulated to enhance ultimate engraftment potential, and understanding stem cell homing is also important to the understanding of stem cell mobilization. Homing is also of potential importance in the recruitment of marrow mesenchymal stem and stromal cells (MSCs) to sites of injury and regeneration. This process is less understood but assumes importance when these cells are used for repair purposes. In this review, the process of HSPC and MSC homing is examined, as are methods to enhance this process.

The bone marrow microenvironment contributes to the regulation of hematopoietic stem cell (HSC) function, though its role in age-associated lineage skewing is poorly understood. Here we show that dysfunction of aged marrow macrophages (Mφs) directs HSC platelet bias. Mφs from the marrow of aged mice and humans exhibited an activated phenotype, with increased expression of inflammatory signals. Aged marrow Mφs also displayed decreased phagocytic function. Senescent neutrophils, typically cleared by marrow Mφs, were markedly increased in aged mice, consistent with functional defects in Mφ phagocytosis and efferocytosis. In aged mice, interleukin-1B (IL-1B) was elevated in the bone marrow, and caspase-1 activity, which can process pro–IL-1B, was increased in marrow Mφs and neutrophils. Mechanistically, IL-1B signaling was necessary and sufficient to induce a platelet bias in HSCs. In young mice, depletion of phagocytic cell populations or loss of the efferocytic receptor Axl expanded platelet-biased HSCs. Our data support a model wherein increased inflammatory signals and decreased phagocytic function of aged marrow Mφs induce the acquisition of platelet bias in aged HSCs. This work highlights the instructive role of Mφs and IL-1B in the age-associated lineage skewing of HSCs, and reveals the therapeutic potential of their manipulation as antigeronic targets.

Bone marrow mesenchymal stromal cells (MSCs) constitute one of the important components of the hematopoietic microenvironmental niche. In vivo studies have shown that depletion of marrow MSCs resulted in reduction of hematopoietic stem cell content, and there is in vitro evidence that marrow MSCs are able to support leukemia progenitor cell proliferation and survival and provide resistance to cytotoxic therapies. How MSCs from leukemia marrow differ from normal counterparts and how they are influenced by the presence of leukemia stem and progenitor cells are still incompletely understood. In this work, we compared normal donor (ND) and acute myelogenous leukemia (AML) derived MSCs and found that AML-MSCs had increased adipogenic potential with improved ability to support survival of leukemia progenitor cells. To identify underlying changes, RNA-Seq analysis was performed. Gene ontology and pathway analysis revealed adipogenesis to be among the set of altered biological pathways dysregulated in AML-MSCs as compared with ND-MSCs. Expression of both SOX9 and EGR2 was decreased in AML-MSCs as compared with ND-MSCs. Increasing expression of SOX9 decreased adipogenic potential of AML-MSCs and decreased their ability to support AML progenitor cells. These findings suggest that AML-MSCs possess adipogenic potential which may enhance support of leukemia progenitor cells.

Chimeric Antigen Receptor T-cell (CAR-T) immunotherapy has emerged as an efficacious and life extending treatment modality with high response rates and durable remissions in patients with relapsed and refractory non-Hodgkin lymphoma (NHL), follicular lymphoma, and B-cell acute lymphoblastic leukemia (B-ALL) as well as in other diseases. Prolonged or recurrent cytopenias after CAR-T therapy have increasingly been reported at varying rates, and the pathogenesis of this complication is not yet well-understood but is likely contributed to by multiple factors. Current studies reported are primarily retrospective, heterogeneous in terms of CAR-Ts used and diseases treated, non-uniform in definitions of cytopenias and durations for end points, and vary in terms of recommended management. Prospective studies and correlative laboratory studies investigating the pathophysiology of prolonged cytopenias will enhance our understanding of this phenomenon. This review summarizes knowledge of these cytopenias to date.

Journal of Medical Internet Research - International Scientific Journal for Medical Research, Information and Communication on the Internet #Preprint #PeerReviewMe: Warning: This is a unreviewed preprint. Readers are warned that the document has not been peer-reviewed by expert/patient reviewers or an academic editor, may contain misleading claims, and is likely to undergo changes before final publication, if accepted, or may have been rejected/withdrawn. Readers with interest and expertise are encouraged to sign up as peer-reviewer, if the paper is within an open peer-review period. Please cite this preprint only for review purposes or for grant applications and CVs (if you are the author). Background: Older patients with cancer are increased risk of adverse outcomes. A geriatric assessment (GA) is a compilation of reliable and validated tools to assess domains that are predictors of morbidity and mortality, and it can be used to guide interventions. However, implementation of GA and GA-driven interventions is low due to resource and time limitations. GA-driven interventions delivered through a mobile application (app) may support the complex needs of older patients with cancer and their caregivers. Objective: We aimed to evaluate the feasibility and usability of a novel mobile app (TouchStream) and to identify barriers to its use. As an exploratory aim, we gathered preliminary data on symptom burden, healthcare utilization, and satisfaction. Methods: In a single-site pilot study, we included patients aged ≥65 years undergoing treatment for systemic cancer and/or their caregivers. TouchStream consists of a mobile app and a Web portal. Patients underwent a GA at baseline with the study team (on paper) and the results were used to guide interventions delivered through the app. A tablet preloaded with the app was provided for use at home for 4 weeks. Feasibility metrics included usability (system usability scale of >68 is considered above average), recruitment, retention (number of subjects consented who completed post-intervention assessments), and percentage (%) of days subjects used the app. For the last 8 patients, we assessed their symptom burden (severity and interference; 17-items scored from 0-10, higher score indicates worse symptoms) using a clinical symptom inventory, healthcare utilization from the electronic medical records, and satisfaction (6 items scored on a 5-point Likert Scale, higher score indicates higher satisfaction; both patients and caregivers) using a modified satisfaction survey. Barriers to use were elicited through interviews. Results: A total of 18 patients (mean age 77, range 68-87) and 13 caregivers (70, 38-81) completed baseline assessment. Recruitment and retention rates were 67% and 80%, respectively. Mean SUS score was 74 for patients and 72 for caregivers. Mean % of days the TouchStream app was used was 79%. Mean symptom severity and interference scores were 1.6 and 2.8 at pre-intervention, and 0.9 and 1.5 at post-intervention, respectively. There was a total of 27 clinic calls during the intervention period and 15 during the post-intervention period (week 5-8). One patient was hospitalized during the intervention period (week 1-4) and two patients during the post-intervention period (week 5-8). Mean satisfaction scores of patients and caregivers with the mobile app were 20.4 and 23.4, respectively. Barriers fell into 3 themes: general experience, design, and functionality. Conclusions: TouchStream is feasible and usable for older patients on cancer treatment and their caregivers. Future studies should evaluate the effects of the TouchStream on symptoms and healthcare utilization in a randomized fashion.