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.
Steps in hematopoietic stem cell (HSC) homing and egress to and from marrow. Homing (left hand panel) occurs in the marrow sinusoidal endothelium. (1) Selectin‐mediated braking or rolling occurs. Selectins involved include P‐selectin which interacts with CD162 and SLex, and E‐selectin which recognizes CD15, SLex, and CD162 on stem cells. (2) HSCs migrate on adhesion ligands presented by the vascular endothelium, so‐called tethering. This involves CD49d‐f, CD11b, and CD11c on the hematopoietic stem and progenitor cells and CD106/fibronectin, laminin, and ICAM‐1 on endothelium as well as numerous other adhesion receptors and their ligands. (3) Changes in integrin conformation facilitate tight adhesion to the endothelial cell. (4) The stem cell then migrates through the endothelial cell cytoplasm or paracellularly. The cell will then migrate through matrix to reach the lodging destination. This is facilitated by CXCL12, c‐kit ligand, cathepsins, and matrix metalloproteinases. Egress (right hand panel) involves: (1) Matrix transmigration in response to chemokine and growth factor effects. Matrix components involved include collagen IV, laminin, fibronectin, hyaluronic acid, and tenascin; among others. (2) Trans‐endothelial migration, and (3) Cell release with disruption of receptor/ligand interactions such as those between between CXCL12 and CXCR4 or CD49d and CD106 (VCAM‐1).
Most forms of chemotherapy employ mechanisms involving induction of oxidative stress, a strategy that can be effective due to the elevated oxidative state commonly observed in cancer cells. However, ...recent studies have shown that relative redox levels in primary tumors can be heterogeneous, suggesting that regimens dependent on differential oxidative state may not be uniformly effective. To investigate this issue in hematological malignancies, we evaluated mechanisms controlling oxidative state in primary specimens derived from acute myelogenous leukemia (AML) patients. Our studies demonstrate three striking findings. First, the majority of functionally defined leukemia stem cells (LSCs) are characterized by relatively low levels of reactive oxygen species (termed “ROS-low”). Second, ROS-low LSCs aberrantly overexpress BCL-2. Third, BCL-2 inhibition reduced oxidative phosphorylation and selectively eradicated quiescent LSCs. Based on these findings, we propose a model wherein the unique physiology of ROS-low LSCs provides an opportunity for selective targeting via disruption of BCL-2-dependent oxidative phosphorylation.
► LSC are prospectively isolated from the bulk tumor on the basis of low ROS levels ► Metabolic dependencies discriminating LSCs, bulk tumor, and normal HSCs are described ► BCL-2 is identified as a regulator of LSC mitochondrial respiration ► BCL-2 pharmacologic inhibitors demonstrate LSC-specific targeting
Human leukemia stem cells upregulate BCL-2 expression as a result of relying on oxidative phosphorylation to produce energy and can therefore be targeted with BCL-2 inhibitors.
The phosphatidylinositol 3-kinase/protein kinase B (Akt)/mechanistic target of rapamycin (PI3K/Akt/mTOR) pathway is amplified in 60–80% of patients with acute myelogenous leukemia (AML). Since this ...complex pathway is crucial to cell functions such as growth, proliferation, and survival, inhibition of this pathway would be postulated to inhibit leukemia initiation and propagation. Inhibition of the mTORC1 pathway has met with limited success in AML due to multiple resistance mechanisms including direct insensitivity of the mTORC1 complex, feedback activation of the PI3k/Akt signaling network, insulin growth factor-1 (IGF-1) activation of PI3K, and others. This review explores the role of mTOR inhibition in AML, mechanisms of resistance, and means to improve outcomes through use of dual mTORC1/2 inhibitors or dual TORC/PI3K inhibitors. How these inhibitors interface with currently available therapies in AML will require additional preclinical experiments and conduct of well-designed clinical trials.
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.
Mounting experimental evidence demonstrates that platelets support cancer metastasis. Within the circulatory system, platelets guard circulating tumor cells (CTCs) from immune elimination and promote ...their arrest at the endothelium, supporting CTC extravasation into secondary sites. Neutralization of CTCs in blood circulation can potentially attenuate metastases to distant organs. Therefore, extensive studies have explored the blockade of platelet–CTC interactions as an anti-metastatic strategy. Such an intervention approach, however, may cause bleeding disorders since the platelet–CTC interactions inherently rely on the blood coagulation cascade including platelet activation. On the other hand, platelets have been genetically engineered to correct inherited bleeding disorders in both animal models and human clinical trials. In this study, inspired by the physical association between platelets and CTCs, platelets were genetically modified to express surface-bound tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a cytokine known to induce apoptosis specifically in tumor cells. The TRAIL-expressing platelets were demonstrated to kill cancer cells in vitro and significantly reduce metastases in a mouse model of prostate cancer metastasis. Our results suggest that using platelets to produce and deliver cancer-specific therapeutics can provide a Trojan-horse strategy of neutralizing CTCs to attenuate metastasis.
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Most cancers evolve over time as patients initially responsive to therapy acquire resistance to the same drugs at relapse. Cancer stem cells have been postulated to represent a therapy-refractory ...reservoir for relapse, but formal proof of this model is lacking. We prospectively characterized leukemia stem cell populations (LSCs) from a well-defined cohort of patients with acute myelogenous leukemia (AML) at diagnosis and relapse to assess the effect of the disease course on these critical populations. Leukemic samples were collected from patients with newly diagnosed AML before therapy and after relapse, and LSC frequency was assessed by limiting dilution analyses. LSC populations were identified using fluorescent-labeled cell sorting and transplantation into immunodeficient NOD/SCID/interleukin 2 receptor γ chain null mice. The surface antigen expression profiles of pretherapy and postrelapse LSCs were determined for published LSC markers. We demonstrate a 9- to 90-fold increase in LSC frequency between diagnosis and relapse. LSC activity at relapse was identified in populations of leukemic blasts that did not demonstrate this activity before treatment and relapse. In addition, we describe genetic instability and exceptional phenotypic changes that accompany the evolution of these new LSC populations. This study is the first to characterize the evolution of LSCs in vivo after chemotherapy, identifying a dramatic change in the physiology of primitive AML cells when the disease progresses. Taken together, these findings provide a new frame of reference by which to evaluate candidate AML therapies in which both disease control and the induction of more advanced forms of disease should be considered.
•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.
Acute myeloid leukemia (AML) represents 80% of acute leukemia in adults and is characterized by clonal expansion of hematopoietic stem cells secondary to genomic mutations, rendering a selective ...growth advantage to the mutant clones. NPM1
is found in around 30% of AML and clinically presents with leukocytosis, high blast percentage and extramedullary involvement. Considered as a "gate-keeper" mutation, NPM1
appears to be a "first hit" in the process of leukemogenesis and development of overt leukemia. Commonly associated with other mutations (e.g., FLT 3, DNMT3A, TET2, SF3B1), NPM1 mutation in AML has an important role in diagnosis, prognosis, treatment and post-treatment monitoring. Several novel therapies targeting NPM1 are being developed in various clinical phases with demonstration of efficacy. In this review, we summarize the pathophysiology of the NPM1 gene mutation in AML, clinical implications and the novel targeted therapies to date.
The myelodysplastic syndromes (MDS) represent neoplasms derived from the expansion of mutated clonal hematopoietic cells which often demonstrate aberrant differentiation potential with resultant ...cytopenias and a propensity to evolve into acute myelogenous leukemia. While multiple mutations have been identified which may serve as drivers of the MDS clone, there is accumulating evidence that MDS clones and subclones are subject to modulation by the marrow microenvironment and its inflammatory milieu. There is also a strong link between autoimmune disorders and MDS. In this review, we examine the role of inflammatory cytokines, toll like receptors, pyroptosis, stromal cells, and cellular inflammatory mediators in MDS initiation, propagation, and progression. These contributions in a background of mutational, epigenetic, and aging changes in the marrow are also reviewed. Such inflammatory mediators may be subject to therapeutic agents which will enhance suppression of the MDS clone with potential to improve therapeutic outcomes in this disease which is usually incurable in aged patients not eligible for stem cell transplantation.
Uproleselan (GMI-1271) is a novel E-selectin antagonist that disrupts cell survival pathways, enhances chemotherapy response, improves survival in mouse xenograft and syngeneic models, and decreases ...chemotherapy toxicity in vivo. A phase 1/2 study evaluated the safety, tolerability, and antileukemic activity of uproleselan (5-20 mg/kg) with MEC (mitoxantrone, etoposide, and cytarabine) among patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). Among the first 19 patients, no dose-limiting toxicities were observed. The recommended phase 2 dose (RP2D) was 10 mg/kg twice daily. An additional 47 patients with R/R AML were treated with uproleselan at the RP2D plus MEC. At the RP2D, the remission rate (complete response CR/CR with incomplete count recovery CRi) was 41% (CR, 35%), and the median overall survival (OS) was 8.8 months. In a separate cohort, 25 newly diagnosed patients age ≥60 years received uproleselan at the RP2D plus cytarabine and idarubicin (7 + 3). In these frontline patients, the CR/CRi rate was 72% (CR, 52%), and the median OS was 12.6 months. The addition of uproleselan was associated with low rates of oral mucositis. E-selectin ligand expression on leukemic blasts was higher in patients with relapsed vs primary refractory AML and in newly diagnosed older patients with high-risk cytogenetics and secondary AML. In the R/R cohort, E-selectin expression >10% was associated with a higher response rate and improved survival. The addition of uproleselan to chemotherapy was well tolerated, with high remission rates, low induction mortality, and low rates of mucositis, providing a strong rationale for phase 3 randomized confirmatory studies. This trial was registered at www.clinicaltrials.gov as #NCT02306291.
•Uproleselan at doses ranging from 5 to 20 mg/kg was well tolerated, with adverse event profile similar to that of background chemotherapy.•Median OS at RP2D (10 mg/kg) in patients with R/R or newly diagnosed AML was 8.8 or 12.6 months, respectively.
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