Angiogenesis in Acute Myeloid Leukemia and Opportunities for Novel Therapies

Acute myeloid leukemia (AML) arises from neoplastic transformation of hematopoietic stem and progenitor cells, and relapsed disease remains one of the greater challenges in treating this hematologic malignancy. This paper focuses on angiogenic aspects of AML including the significance and prognostic value of bone marrow microvessel density and circulating cytokine levels. We show three general mechanisms whereby AML exploits angiogenic pathways, including direct induction of angiogenesis, paracrine regulation, and autocrine stimulation. We also present early evidence that leukemia cells contribute directly to vascular endothelia. Novel treatment strategies are proposed, and a review of relevant antiangiogenic clinical trials is presented. By understanding how blood vessels can serve as a reservoir for refractory and relapsed AML, new diagnostics and promising treatment strategies can be developed

The thrombopoietin receptor, c-Mpl, is a selective surface marker for human hematopoietic stem cells

BACKGROUND: Thrombopoietin (TPO), the primary cytokine regulating megakaryocyte proliferation and differentiation, exerts significant influence on other hematopoietic lineages as well, including erythroid, granulocytic and lymphoid lineages. We previously demonstrated that the receptor for TPO, c-mpl, is expressed by a subset of human adult bone marrow hematopoietic stem/progenitor cells (HSC/PC) that are enriched for long-term multilineage repopulating ability in the SCID-hu Bone in vivo model of human hematopoiesis. METHODS: Here, we employ flow cytometry and an anti-c-mpl monoclonal antibody to comprehensively define the surface expression pattern of c-mpl in four differentiation stages of human CD34(+ )HSC/PC (I: CD34(+)38(--), II: CD34(+)38(dim), III: CD34(+)38(+), IV: CD34(dim)38(+)) for the major sources of human HSC: fetal liver (FL), umbilical cord blood (UCB), adult bone marrow (ABM), and cytokine-mobilized peripheral blood stem cells (mPBSC). We use a surrogate in vivo model of human thymopoiesis, SCID-hu Thy/Liv, to compare the capacity of c-mpl(+ )vs. c-mpl(-- )CD34(+)38(--/dim )HSC/PC for thymocyte reconstitution. RESULTS: For all tissue sources, the percentage of c-mpl(+ )cells was significantly highest in stage I HSC/PC (FL 72 ± 10%, UCB 67 ± 19%, ABM 82 ± 16%, mPBSC 71 ± 15%), and decreased significantly through stages II, III, and IV ((FL 3 ± 3%, UCB 8 ± 13%, ABM 0.6 ± 0.6%, mPBSC 0.2 ± 0.1%) [ANOVA: P < 0.0001]. The relative median fluorescence intensity of c-mpl expression was similarly highest in stage I, decreasing through stage IV [ANOVA: P < 0.0001]. No significant differences between tissue sources were observed for either % c-mpl(+ )cells [P = 0.89] or intensity of c-mpl expression [P = 0.21]. Primary Thy/Liv grafts injected with CD34(+)38(--/dim)c-mpl(+ )cells showed slightly higher levels of donor HLA(+ )thymocyte reconstitution vs. CD34(+)38(--/dim)c-mpl(--)-injected grafts and non-injected controls (c-mpl(+ )vs. c-mpl(--): CD2(+ )6.8 ± 4.5% vs. 2.8 ± 3.3%, CD4(+)8(-- )54 ± 35% vs. 31 ± 29%, CD4(--)8(+ )29 ± 19% vs. 18 ± 14%). CONCLUSION: These findings support the hypothesis that the TPO receptor, c-mpl, participates in the regulation of primitive human HSC from mid-fetal through adult life. This study extends our previous work documenting human B-lineage, myeloid and CD34(+ )cell repopulation by c-mpl(+ )progenitors to show that c-mpl(+ )HSC/PC are also capable of significant T-lineage reconstitution in vivo. These results suggest that c-mpl merits consideration as a selective surface marker for the identification and isolation of human HSC in both basic research and clinical settings

Oncolytic Virotherapy for Hematological Malignancies

Hematological malignancies such as leukemias, lymphomas, multiple myeloma (MM), and the myelodysplastic syndromes (MDSs) primarily affect adults and are difficult to treat. For high-risk disease, hematopoietic stem cell transplant (HCT) can be used. However, in the setting of autologous HCT, relapse due to contamination of the autograft with cancer cells remains a major challenge. Ex vivo manipulations of the autograft to purge cancer cells using chemotherapies and toxins have been attempted. Because these past strategies lack specificity for malignant cells and often impair the normal hematopoietic stem and progenitor cells, prior efforts to ex vivo purge autografts have resulted in prolonged cytopenias and graft failure. The ideal ex vivo purging agent would selectively target the contaminating cancer cells while spare normal stem and progenitor cells and would be applied quickly without toxicities to the recipient. One agent which meets these criteria is oncolytic viruses. This paper details experimental progress with reovirus, myxoma virus, measles virus, vesicular stomatitis virus, coxsackievirus, and vaccinia virus as well as requirements for translation of these results to the clinic

Identification of Bone Marrow Cell Subpopulations Associated With Improved Functional Outcomes in Patients With Chronic Left Ventricular Dysfunction: An Embedded Cohort Evaluation of the FOCUS-CCTRN Trial

In the current study, we sought to identify bone marrow-derived mononuclear cell (BM-MNC) subpopulations associated with a combined improvement in left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), and maximal oxygen consumption (VO2 max) in patients with chronic ischemic cardiomyopathy 6 months after receiving transendocardial injections of autologous BM-MNCs or placebo. For this prospectively planned analysis, we conducted an embedded cohort study comprising 78 patients from the FOCUS-Cardiovascular Cell Therapy Research Network (CCTRN) trial. Baseline BM-MNC immunophenotypes and progenitor cell activity were determined by flow cytometry and colony-forming assays, respectively. Previously stable patients who demonstrated improvement in LVEF, LVESV, and VO2 max during the 6-month course of the FOCUS-CCTRN study (group 1, n = 17) were compared to those who showed no change or worsened in one to three of these endpoints (group 2, n = 61) and to a subset of patients from group 2 who declined in all three functional endpoints (group 2A, n = 11). Group 1 had higher frequencies of B-cell and CXCR4(+) BM-MNC subpopulations at study baseline than group 2 or 2A. Furthermore, patients in group 1 had fewer endothelial colony-forming cells and monocytes/macrophages in their bone marrow than those in group 2A. To our knowledge, this is the first study to show that in patients with ischemic cardiomyopathy, certain bone marrow-derived cell subsets are associated with improvement in LVEF, LVESV, and VO2 max at 6 months. These results suggest that the presence of both progenitor and immune cell populations in the bone marrow may influence the natural history of chronic ischemic cardiomyopathy-even in stable patients. Thus, it may be important to consider the bone marrow composition and associated regenerative capacity of patients when assigning them to treatment groups and evaluating the results of cell therapy trials

Impact of the COVID-19 Pandemic on Colorectal and Prostate Cancer Screening in a Large U.S. Health System

During the first year of the coronavirus disease 2019 (COVID-19) pandemic, prevention measures included quarantining and facility closures. Because cancer screening is dependent on interventions in facilities, the extent of the COVID-19 impact on screening was questioned. A claims registry from a large health system was queried for colorectal and prostate cancer screening. A screening gap and screening loss ratio were calculated by comparing 2020 screening to historical reference years. All cancer screenings decreased in the first four months of the pandemic. Colorectal cancer screening returned to baseline in the latter six months of 2020. Prostate cancer screening exceeded baseline in the latter six months, but with a lesser gain than previous years. Populations disproportionately affected by decreased cancer screening included men and black people. To catch-up after the initial deficit in screening, it is estimated that the rate of colorectal cancer screening needs to increase by 50%

Functional Dependency Analysis Identifies Potential Druggable Targets in Acute Myeloid Leukemia

Refractory disease is a major challenge in treating patients with acute myeloid leukemia (AML). Whereas the armamentarium has expanded in the past few years for treating AML, long-term survival outcomes have yet to be proven. To further expand the arsenal for treating AML, we searched for druggable gene targets in AML by analyzing screening data from a lentiviral-based genome-wide pooled CRISPR-Cas9 library and gene knockout (KO) dependency scores in 15 AML cell lines (HEL, MV411, OCIAML2, THP1, NOMO1, EOL1, KASUMI1, NB4, OCIAML3, MOLM13, TF1, U937, F36P, AML193, P31FUJ). Ninety-four gene KOs met the criteria of (A) specifically essential to AML cell survival, (B) non-essential in non-AML cells, and (C) druggable according to three-dimensional (3D) modeling or ligand-based druggability scoring. Forty-four of 94 gene-KOs (47%) had an already-approved drug match and comprised a drug development list termed &ldquo;deKO.&rdquo; Fifty of 94 gene-KOs (53%) had no drug in development and comprised a drug discovery list termed &ldquo;disKO.&rdquo; STRING analysis and gene ontology categorization of the disKO targets preferentially cluster in the metabolic processes of UMP biosynthesis, IMP biosynthesis, dihydrofolate metabolism, pyrimidine nucleobase biosynthesis, vitellogenesis, and regulation of T cell differentiation and hematopoiesis. Results from this study serve as a testable compendium of AML drug targets that, after validation, may be translated into new therapeutics

Implementation of Cancer Plans in the United States: A Review

State cancer plans facilitate prioritization and stakeholder engagement in preventing and controlling cancer. Implementation plans further help stakeholders prioritize efforts, reduce redundancy, and find opportunities for work synergies. A review of cancer plan implementations plans was performed in the development of an implementation plan for the Florida Cancer Plan. This review sought to identify, characterize, and summarize the use of implementation plans that support comprehensive cancer control activities. Although 100% of states and territories published a cancer plan and 78% of states provided funding for implementing their state cancer plans, only 32% published an implementation plan. Commonalities and unique features of state cancer plan implementations are presented and discussed. An example implementation plan is provided for states without a plan to model

Implementation of Cancer Plans in the United States: A Review

State cancer plans facilitate prioritization and stakeholder engagement in preventing and controlling cancer. Implementation plans further help stakeholders prioritize efforts, reduce redundancy, and find opportunities for work synergies. A review of cancer plan implementations plans was performed in the development of an implementation plan for the Florida Cancer Plan. This review sought to identify, characterize, and summarize the use of implementation plans that support comprehensive cancer control activities. Although 100% of states and territories published a cancer plan and 78% of states provided funding for implementing their state cancer plans, only 32% published an implementation plan. Commonalities and unique features of state cancer plan implementations are presented and discussed. An example implementation plan is provided for states without a plan to model