Uncoupling DNA damage from chromatin damage to detoxify doxorubicin.

The anthracycline doxorubicin (Doxo) and its analogs daunorubicin (Daun), epirubicin (Epi), and idarubicin (Ida) have been cornerstones of anticancer therapy for nearly five decades. However, their clinical application is limited by severe side effects, especially dose-dependent irreversible cardiotoxicity. Other detrimental side effects of anthracyclines include therapy-related malignancies and infertility. It is unclear whether these side effects are coupled to the chemotherapeutic efficacy. Doxo, Daun, Epi, and Ida execute two cellular activities: DNA damage, causing double-strand breaks (DSBs) following poisoning of topoisomerase II (Topo II), and chromatin damage, mediated through histone eviction at selected sites in the genome. Here we report that anthracycline-induced cardiotoxicity requires the combination of both cellular activities. Topo II poisons with either one of the activities fail to induce cardiotoxicity in mice and human cardiac microtissues, as observed for aclarubicin (Acla) and etoposide (Etop). Further, we show that Doxo can be detoxified by chemically separating these two activities. Anthracycline variants that induce chromatin damage without causing DSBs maintain similar anticancer potency in cell lines, mice, and human acute myeloid leukemia patients, implying that chromatin damage constitutes a major cytotoxic mechanism of anthracyclines. With these anthracyclines abstained from cardiotoxicity and therapy-related tumors, we thus uncoupled the side effects from anticancer efficacy. These results suggest that anthracycline variants acting primarily via chromatin damage may allow prolonged treatment of cancer patients and will improve the quality of life of cancer survivors.

Distinct bone marrow immunophenotypic features define the splicing factor 3B subunit 1 (SF3B1)-mutant myelodysplastic syndromes subtype.

Splicing factor 3B subunit 1 (SF3B1) mutations define a distinct myelodysplastic syndromes (MDS) patient group with a relatively favourable disease course and high response rates to luspatercept. Few data are available on bone marrow phenotype beyond ring sideroblasts in this subgroup of patients with MDS. In the present study, we identified immunophenotypic erythroid, myelomonocyte and progenitor features associated with SF3B1 mutations. In addition, we illustrate that SF3B1-mutation type is associated with distinct immunophenotypic features, and show the impact of co-occurrence of a SF3B1 mutation and a deletion of chromosome 5q on bone marrow immunophenotype. These genotype-phenotype associations and phenotypic subtypes within SF3B1-MDS provide leads that may further refine prognostication and therapeutic strategies for this particular MDS subgroup.

Bimodal expression of potential drug target CLL-1 (CLEC12A) on CD34+ blasts of AML patients.

OBJECTIVES: This study aims to retrospectively assess C-lectin-like molecule 1 (CLL-1) bimodal expression on CD34+ blasts in acute myeloid leukemia (AML) patients (total N = 306) and explore potential CLL-1 bimodal associations with leukemia and patient-specific characteristics. METHODS: Flow cytometry assays were performed to assess the deeper immunophenotyping of CLL-1 bimodality. Cytogenetic analysis was performed to characterize the gene mutation on CLL-1-negative subpopulation of CLL-1 bimodal AML samples. RESULTS: The frequency of a bimodal pattern of CLL-1 expression of CD34+ blasts ranged from 8% to 65% in the different cohorts. Bimodal CLL-1 expression was most prevalent in patients with MDS-related AML (P = .011), ELN adverse risk (P = .002), NPM1 wild type (WT, P = .049), FLT3 WT (P = .035), and relatively low percentages of leukemia-associated immunophenotypes (P = .006). Additional immunophenotyping analysis revealed the CLL-1- subpopulation may consist of pre-B cells, immature myeloblasts, and hematopoietic stem cells. Furthermore, (pre)-leukemic mutations were detected in both CLL-1+ and CLL-1- subfractions of bimodal samples (N = 3). CONCLUSIONS: C-lectin-like molecule 1 bimodality occurs in about 25% of AML patients and the CLL-1- cell population still contains malignant cells, hence it may potentially limit the effectiveness of CLL-1-targeted therapies and warrant further investigation.

Impact of organizational context on patient outcomes in a proactive primary care program:a longitudinal observational study.

BACKGROUND: The effectiveness of health care interventions is co-determined by contextual factors. Unknown is the extent of this impact on patient outcomes. Therefore, the aim of this study is to explore which characteristics of general practices are associated with patient outcomes in a proactive primary care program, the U-PROFIT 2.0. METHODS: A longitudinal observational study was conducted from January 2016 till October 2017. Two questionnaires were send out, one to collect characteristics of general practices such as practice neighbourhood socio-economic status, general practice versus healthcare centre (involving multiple primary care professionals), and professional- frail older patient ratio per practice of general practitioners and practice nurses. Regarding delivering the program, the practice or district nurse who delivered the program, number of years since the start of the implementation, and choice of age threshold for frailty screening were collected. Patient outcomes collected by the second questionnaire and send to frail patients were daily functioning, hospital admissions, emergency department visits, and general practice out-of-hours consultations. Linear and generalized linear mixed models were used. RESULTS: A total of 827 frail older people were included at baseline. Delivery of the program by a district nurse compared to a practice nurse was significantly associated with a decrease in daily functioning on patient-level (ß = 2.19; P = < 0.001). Duration since implementation of 3 years compared to 9 years was significantly associated with less out-of-hours consultations to a general practice (OR 0.11; P = 0.001). Applying frailty screening from the age of 75 compared to those targeted from the age of 60 showed a significant increase in emergency visits (OR 5.26; P = 0.03). CONCLUSION: Three associations regarding the organizational context 1) the nurse who delivered the program, 2) the number of years the program was implemented and 3) the age threshold for defining a frail patient are significant and clinically relevant for frail patients that receive a proactive primary care program. In general, contextual factors need more attention when implementing complex primary care programs which can result in better balanced choices to enhance effective proactive care for older people living in the community.

Primary acute myeloid leukemia cells with overexpression of EVI-1 are sensitive to all-trans retinoic acid.

Enhanced expression of ecotropic viral integration site 1 (EVI-1) occurs in ∼10% of acute myeloid leukemia (AML) patients and is associated with a very poor disease outcome. Patients with EVI-1-positive AML have poor initial responses to chemotherapy and high relapse rates, indicating an urgent need for alternative treatment strategies improving clinical outcome for these patients. Because treatment of acute promyelocytic patients with all-trans retinoic acid (ATRA) has improved the survival of these patients substantially, we investigated whether ATRA might also be effective for the subgroup of AML patients with EVI-1 overexpression. Here, we show that a substantial part of the EVI-1-positive AML cases respond to ATRA by induction of differentiation and decreased clonogenic capacity of myeloid blasts. Most importantly, we demonstrate that in vivo treatment of primary EVI-1-positive AML with ATRA leads to a significant reduction in leukemic engraftment. Altogether, our results show that a considerable part of the EVI-1-positive primary AML cases are sensitive to ATRA, suggesting that combining ATRA with the currently used conventional chemotherapy might be a promising treatment strategy decreasing relapse rates and enhancing complete remissions in this poor prognostic subgroup of AML patients.

Immunophenotypic aberrant hematopoietic stem cells in myelodysplastic syndromes: a biomarker for leukemic progression.

Myelodysplastic syndromes (MDS) comprise hematological disorders that originate from the neoplastic transformation of hematopoietic stem cells (HSCs). However, discrimination between HSCs and their neoplastic counterparts in MDS-derived bone marrows (MDS-BMs) remains challenging. We hypothesized that in MDS patients immature CD34+CD38- cells with aberrant expression of immunophenotypic markers reflect neoplastic stem cells and that their frequency predicts leukemic progression. We analyzed samples from 68 MDS patients and 53 controls and discriminated HSCs from immunophenotypic aberrant HSCs (IA-HSCs) expressing membrane aberrancies (CD7, CD11b, CD22, CD33, CD44, CD45RA, CD56, CD123, CD366 or CD371). One-third of the MDS-BMs (23/68) contained IA-HSCs. The presence of IA-HSCs correlated with perturbed hematopoiesis (disproportionally expanded CD34+ subsets beside cytopenias) and an increased hazard of leukemic progression (HR = 25, 95% CI: 2.9-218) that was independent of conventional risk factors. At 2 years follow-up, the sensitivity and specificity of presence of IA-HSCs for predicting leukemic progression was 83% (95% CI: 36-99%) and 71% (95% CI: 58-81%), respectively. In a selected cohort (n = 10), most MDS-BMs with IA-HSCs showed genomic complexity and high human blast counts following xenotransplantation into immunodeficient mice, contrasting MDS-BMs without IA-HSCs. This study demonstrates that the presence of IA-HSCs within MDS-BMs predicts leukemic progression, indicating the clinical potential of IA-HSCs as a prognostic biomarker.

Characteristics of leukemic stem cells in acute leukemia and potential targeted therapies for their specific eradication.

In acute myeloid leukemia (AML), a small cell population that contains stem cell features such as lack of differentiation, self-renewal potential, and drug resistance, can be identified. These so-called leukemic stem cells (LSCs) are thought to be responsible for relapse initiation after initial treatment leading to successful eradication of the bulk AML cell population. Since many studies have aimed to characterize and eliminate LSCs to prevent relapse and increase survival rates of patients, LSCs are one of the best characterized cancer stem cells. The specific elimination of LSCs, while sparing the healthy normal hematopoietic stem cells (HSCs), is one of the major challenges in the treatment of leukemia. This review focuses on several surface markers and intracellular transcription factors that can distinguish AML LSCs from HSCs and, therefore, specifically eliminate these stem cell-like leukemic cells. Moreover, previous and ongoing clinical trials of acute leukemia patients treated with therapies targeting these markers are discussed. In contrast to knowledge on LSCs in AML, insight into LSCs in acute lymphoid leukemia (ALL) is limited. This review therefore also addresses the latest insight into LSCs in ALL.

Targeting Acute Myeloid Leukemia with Venetoclax; Biomarkers for Sensitivity and Rationale for Venetoclax-Based Combination Therapies.

Venetoclax is a BCL-2 inhibitor that effectively improves clinical outcomes in newly diagnosed, relapsed and refractory acute myeloid leukemia (AML) patients, with complete response rates (with and without complete blood count recovery) ranging between 34-90% and 21-33%, respectively. Here, we aim to give an overview of the efficacy of venetoclax-based therapy for AML patients, as compared to standard chemotherapy, and on factors and mechanisms involved in venetoclax sensitivity and resistance in AML (stem) cells, with the aim to obtain a perspective of response biomarkers and combination therapies that could enhance the sensitivity of AML cells to venetoclax. The presence of molecular aberrancies can predict responses to venetoclax, with a higher response in NPM1-, IDH1/2-, TET2- and relapsed or refractory RUNX1-mutated AML. Decreased sensitivity to venetoclax was observed in patients harboring FLT3-ITD, TP53, K/NRAS or PTPN11 mutations. Moreover, resistance to venetoclax was observed in AML with a monocytic phenotype and patients pre-treated with hypomethylating agents. Resistance to venetoclax can arise due to mutations in BCL-2 or pro-apoptotic proteins, an increased dependency on MCL-1, and usage of additional/alternative sources for energy metabolism, such as glycolysis and fatty acid metabolism. Clinical studies are testing combination therapies that may circumvent resistance, including venetoclax combined with FLT3- and MCL-1 inhibitors, to enhance venetoclax-induced cell death. Other treatments that can potentially synergize with venetoclax, including MEK1/2 and mitochondrial complex inhibitors, need to be evaluated in a clinical setting.

Exploring the development, evaluation and implementation of complex health interventions to prevent early childhood caries in preschool children: A scoping review protocol.

OBJECTIVE: This scoping review aims to identify complex health interventions (CHI's) to prevent early childhood caries (ECC), explore the level of complexity of the identified CHI's, and explore the details of their development, evaluation, and implementation. INTRODUCTION: Many interventions to prevent ECC have multiple interacting components and can be seen as CHI's. Recent reviews on these interventions have found inconclusive effects, which may be due to differences in the development, evaluation, and implementation of CHI's. INCLUSION CRITERIA: This scoping review will consider clinical trials reporting CHI's to prevent ECC that starts during pregnancy or in the first year of life. Studies in the English language will be included regardless of the country of origin, sociocultural setting, or context. METHODS: This review will follow the Joanna Briggs Institute methodology for scoping reviews. An initial search of PubMed identified keywords and Medical Subject Headings terms. A second search of PubMed, Embase, Clarivate Analytics/Web of Science Core Collection, ClinicalTrials.gov, and the Wiley/Cochrane Library will follow. Two independent reviewers will perform title and abstract screening, retrieve and review full-text studies, and extract data. The reference lists of all included sources will be screened for additional CHI's or relevant publications about a specific CHI. Data charting will be utilised based on study characteristics and intervention complexity. A 39-item instrument will be used to explore the details in the description of the CHI's development, evaluation, and implementation. The results will be presented in tables, visual outputs, and a narrative summary in response to the review questions. DISCUSSION: The proposed review will generate evidence which may provide a direction for the future design of studies on CHI's to prevent ECC and more complete information for those who want to adopt successful interventions to prevent ECC.

Targeting histone methylation to reprogram the transcriptional state that drives survival of drug-tolerant myeloid leukemia persisters.

Although chemotherapy induces complete remission in the majority of acute myeloid leukemia (AML) patients, many face a relapse. This relapse is caused by survival of chemotherapy-resistant leukemia (stem) cells (measurable residual disease; MRD). Here, we demonstrate that the anthracycline doxorubicin epigenetically reprograms leukemia cells by inducing histone 3 lysine 27 (H3K27) and H3K4 tri-methylation. Within a doxorubicin-sensitive leukemia cell population, we identified a subpopulation of reversible anthracycline-tolerant cells (ATCs) with leukemic stem cell (LSC) features lacking doxorubicin-induced H3K27me3 or H3K4me3 upregulation. These ATCs have a distinct transcriptional landscape than the leukemia bulk and could be eradicated by KDM6 inhibition. In primary AML, reprogramming the transcriptional state by targeting KDM6 reduced MRD load and survival of LSCs residing within MRD, and enhanced chemotherapy response in vivo. Our results reveal plasticity of anthracycline resistance in AML cells and highlight the potential of transcriptional reprogramming by epigenetic-based therapeutics to target chemotherapy-resistant AML cells.

Escape From Treatment; the Different Faces of Leukemic Stem Cells and Therapy Resistance in Acute Myeloid Leukemia.

Standard induction chemotherapy, consisting of an anthracycline and cytarabine, has been the first-line therapy for many years to treat acute myeloid leukemia (AML). Although this treatment induces complete remissions in the majority of patients, many face a relapse (adaptive resistance) or have refractory disease (primary resistance). Moreover, older patients are often unfit for cytotoxic-based treatment. AML relapse is due to the survival of therapy-resistant leukemia cells (minimal residual disease, MRD). Leukemia cells with stem cell features, named leukemic stem cells (LSCs), residing within MRD are thought to be at the origin of relapse initiation. It is increasingly recognized that leukemia "persisters" are caused by intra-leukemic heterogeneity and non-genetic factors leading to plasticity in therapy response. The BCL2 inhibitor venetoclax, combined with hypomethylating agents or low dose cytarabine, represents an important new therapy especially for older AML patients. However, often there is also a small population of AML cells refractory to venetoclax treatment. As AML MRD reflects the sum of therapy resistance mechanisms, the different faces of treatment "persisters" and LSCs might be exploited to reach an optimal therapy response and prevent the initiation of relapse. Here, we describe the different epigenetic, transcriptional, and metabolic states of therapy sensitive and resistant AML (stem) cell populations and LSCs, how these cell states are influenced by the microenvironment and affect treatment outcome of AML. Moreover, we discuss potential strategies to target dynamic treatment resistance and LSCs.

Implementation of an interprofessional collaboration in practice program: a feasibility study using social network analysis.

BACKGROUND: Due to multimorbidity and geriatric problems, older people often require both psychosocial and medical care. Collaboration between medical and social professionals is a prerequisite to deliver high-quality care for community-living older people. Effective, safe, and person-centered care relies on skilled interprofessional collaboration and practice. Little is known about interprofessional education to increase interprofessional collaboration in practice (IPCP) in the context of community care for older people. This study examines the feasibility of the implementation of an IPCP program in three community districts and determines its potential to increase interprofessional collaboration between primary healthcare professionals caring for older people. METHOD: A feasibility study was conducted to determine the acceptability and feasibility of data collection and analysis regarding interprofessional collaboration in network development. A questionnaire was used to measure the learning experience and the acquisition of knowledge and skills regarding the program. Network development was assessed by distributing a social network survey among professionals attending the program as well as professionals not attending the program at baseline and 5.5 months after. Network development was determined by calculating the number, reciprocity, value, and diversity of contacts between professionals using social network analysis. RESULTS: The IPCP program was found to be instructive and the knowledge and skills gained were applicable in practice. Social network analysis was feasible to conduct and revealed a spill-over effect regarding network development. Program participants, as well as non-program participants, had larger, more reciprocal, and more diverse interprofessional networks than they did before the program. CONCLUSIONS: This study showed the feasibility of implementing an IPCP program in terms of acceptability, feasibility of data collection, and social network analysis to measure network development, and indicated potential to increase interprofessional collaboration between primary healthcare professionals. Both program participants and non-program participants developed a larger, more collaborative, and diverse interprofessional network.

How can we build and maintain the resilience of our health care professionals during COVID-19? Recommendations based on a scoping review.

OBJECTIVE: To explore how to build and maintain the resilience of frontline healthcare professionals exposed to COVID-19 outbreak working conditions. DESIGN: Scoping review supplemented with expert interviews to validate the findings. SETTING: Hospitals. METHODS: We searched PubMed, Embase, PsycINFO, CINAHL, bioRxiv and medRxiv systematically and grey literature for articles focusing on the impact of COVID-19-like working conditions on the physical and/or mental health of healthcare professionals in a hospital setting. Articles using an empirical design about determinants or causes of physical and/or mental health and about interventions, measures and policies to preserve physical and/or mental health were included. Four experts were interviewed to reflect on the results from the scoping review. RESULTS: In total, 4471 records were screened leading to an inclusion of 73 articles. Recommendations prior to the outbreak fostering resilience included optimal provision of education and training, resilience training and interventions to create a feeling of being prepared. Recommendations during the outbreak consisted of (1) enhancing resilience by proper provision of information, psychosocial support and treatment (eg, create enabling conditions such as forming a psychosocial support team), monitoring the health status of professionals and using various forms and content of psychosocial support (eg, encouraging peer support, sharing and celebrating successes), (2) tasks and responsibilities, in which attention should be paid to kind of tasks, task mix and responsibilities as well as the intensity and weight of these tasks and (3) work patterns and working conditions. Findings of the review were validated by experts. CONCLUSIONS: Recommendations were developed on how to build and maintain resilience of frontline healthcare professionals exposed to COVID-19 outbreak working conditions. These practical and easy to implement recommendations can be used by hospitals and other healthcare organisations to foster and preserve short-term and long-term physical and mental health and employability of their professionals.

The Novel Oral BET-CBP/p300 Dual Inhibitor NEO2734 Is Highly Effective in Eradicating Acute Myeloid Leukemia Blasts and Stem/Progenitor Cells.

Acute myeloid leukemia (AML) is a disease characterized by transcriptional dysregulation that results in a block in differentiation and aberrant self-renewal. Inhibitors directed to epigenetic modifiers, aiming at transcriptional reprogramming of AML cells, are currently in clinical trials for AML patients. Several of these inhibitors target bromodomain and extraterminal domain (BET) proteins, cyclic AMP response binding protein-binding protein (CBP), and the E1A-interacting protein of 300 kDa (p300), affecting histone acetylation. Unfortunately, single epigenetic inhibitors showed limited efficacy due to appearance of resistance and lack of effective eradication of leukemic stem cells. Here, we describe the efficacy of 2 novel, orally available inhibitors targeting both the BET and CBP/p300 proteins, NEO1132 and NEO2734, in primary AML. NEO2734 and NEO1132 efficiently reduced the viability of AML cell lines and primary AML cells by inducing apoptosis. Importantly, both NEO drugs eliminated leukemic stem/progenitor cells from AML patient samples, and NEO2734 increased the effectiveness of combination chemotherapy treatment in an in vivo AML patient-derived mouse model. Thus, dual inhibition of BET and CBP/p300 using NEO2734 is a promising therapeutic strategy for AML patients, making it a focus for clinical translation.

PCR-Free Shallow Whole Genome Sequencing for Chromosomal Copy Number Detection from Plasma of Cancer Patients Is an Efficient Alternative to the Conventional PCR-Based Approach.

Somatic copy number alterations can be detected in cell-free DNA (cfDNA) by shallow whole genome sequencing (sWGS). PCR is typically included in library preparations, but a PCR-free method could serve as a high-throughput alternative. To evaluate a PCR-free method for research and diagnostics, archival peripheral blood or bone marrow plasma samples, collected in EDTA- or lithium-heparin-containing tubes, were collected from patients with non-small-cell lung cancer (n = 10 longitudinal samples; 4 patients), B-cell lymphoma (n = 31), and acute myeloid leukemia (n = 15), or from healthy donors (n = 14). sWGS was performed on PCR-free and PCR library preparations, and the mapping quality, percentage of unique reads, genome coverage, fragment lengths, and copy number profiles were compared. The percentage of unique reads was significantly higher for PCR-free method compared with PCR method, independent of the type of collection tube: EDTA PCR-free method, 96.4% (n = 35); EDTA PCR method, 85.1% (n = 32); heparin PCR-free method, 94.5% (n = 25); and heparin PCR method, 89.4% (n = 10). All other evaluated metrics were highly comparable for PCR-free and PCR library preparations. These results demonstrate the feasibility of somatic copy number alteration detection by PCR-free sWGS using cfDNA from plasma collected in EDTA- or lithium-heparin-containing tubes and pave the way for an automated cfDNA analysis workflow for samples from cancer patients.

Value of social network analysis for developing and evaluating complex healthcare interventions: a scoping review.

OBJECTIVES: Most complex healthcare interventions target a network of healthcare professionals. Social network analysis (SNA) is a powerful technique to study how social relationships within a network are established and evolve. We identified in which phases of complex healthcare intervention research SNA is used and the value of SNA for developing and evaluating complex healthcare interventions. METHODS: A scoping review was conducted using the Arksey and O'Malley methodological framework. We included complex healthcare intervention studies using SNA to identify the study characteristics, level of complexity of the healthcare interventions, reported strengths and limitations, and reported implications of SNA. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews 2018 was used to guide the reporting. RESULTS: Among 2466 identified studies, 40 studies were selected for analysis. At first, the results showed that SNA seems underused in evaluating complex intervention research. Second, SNA was not used in the development phase of the included studies. Third, the reported implications in the evaluation and implementation phase reflect the value of SNA in addressing the implementation and population complexity. Fourth, pathway complexity and contextual complexity of the included interventions were unclear or unable to access. Fifth, the use of a mixed methods approach was reported as a strength, as the combination and integration of a quantitative and qualitative method clearly establishes the results. CONCLUSION: SNA is a widely applicable method that can be used in different phases of complex intervention research. SNA can be of value to disentangle and address the level of complexity of complex healthcare interventions. Furthermore, the routine use of SNA within a mixed method approach could yield actionable insights that would be useful in the transactional context of complex interventions.

IGFBP7 activates retinoid acid-induced responses in acute myeloid leukemia stem and progenitor cells.

Treatment of acute promyelocytic leukemia (APL) with all-trans retinoic acid (ATRA) in combination with low doses of arsenic trioxide or chemotherapy leads to exceptionally high cure rates (>90%). ATRA forces APL cells into differentiation and cell death. Unfortunately, ATRA-based therapy has not been effective among any other acute myeloid leukemia (AML) subtype, and long-term survival rates remain unacceptably low; only 30% of AML patients survive 5 years after diagnosis. Here, we identified insulin-like growth factor binding protein 7 (IGFBP7) as part of ATRA-induced responses in APL cells. Most importantly, we observed that addition of recombinant human IGFBP7 (rhIGFBP7) increased ATRA-driven responses in a subset of non-APL AML samples: those with high RARA expression. In nonpromyelocytic AML, rhIGFBP7 treatment induced a transcriptional program that sensitized AML cells for ATRA-induced differentiation, cell death, and inhibition of leukemic stem/progenitor cell survival. Furthermore, the engraftment of primary AML in mice was significantly reduced following treatment with the combination of rhIGFBP7 and ATRA. Mechanistically, we showed that the synergism of ATRA and rhIGFBP7 is due, at least in part, to reduction of the transcription factor GFI1. Together, these results suggest a potential clinical utility of IGFBP7 and ATRA combination treatment to eliminate primary AML (leukemic stem/progenitor) cells and reduce relapse in AML patients.

LKB1 tumor suppressor protein: PARtaker in cell polarity.

The LKB1 (also called serine/threonine kinase 11) tumor suppressor gene was cloned in 1998 by linkage analysis of Peutz-Jeghers cancer syndrome patients. Mammalian LKB1 has been implicated as a regulator of multiple biological processes and signaling pathways, including the control of cell-cycle arrest, p53-mediated apoptosis, Wnt signaling, transforming growth factor (TGF)-beta signaling, ras-induced cell transformation, and energy metabolism. The Caenorhabditis elegans and Drosophila melanogaster LKB1 homologs, termed PAR4 and dLKB1, respectively, regulate cell polarity. Recently, mammalian LKB1 was found to be active only in a complex with two other proteins--STRAD and MO25--and to induce complete polarization of intestinal epithelial cells in a cell-autonomous fashion. In this article, we summarize the findings regarding LKB1 over the past six years. In addition, we discuss LKB1 in polarity in the context of both the other PAR proteins and its tumor suppressive activities.

VEGFC Antibody Therapy Drives Differentiation of AML.

High expression of VEGFC predicts adverse prognosis in acute myeloid leukemia (AML). We therefore explored VEGFC-targeting efficacy as an AML therapy using a VEGFC mAb. VEGFC antibody therapy enforced myelocytic differentiation of clonal CD34+ AML blasts. Treatment of CD34+ AML blasts with the antibody reduced expansion potential by 30% to 50% and enhanced differentiation via FOXO3A suppression and inhibition of MAPK/ERK proliferative signals. VEGFC antibody therapy also accelerated leukemia cell differentiation in a systemic humanized AML mouse model. Collectively, these results define a regulatory function of VEGFC in CD34+ AML cell fate decisions via FOXO3A and serve as a new potential differentiation therapy for patients with AML.Significance: These findings reveal VEGFC targeting as a promising new differentiation therapy in AML. Cancer Res; 78(20); 5940-8. ©2018 AACR.