"It feels like you have to choose one or the other": a qualitative analysis of obstetrician focus groups on periviability counseling.

OBJECTIVES: The objective of this study was to gain knowledge and ascertain challenges about periviability counseling among obstetricians to inform curricular development. METHODS: Focus groups were utilized. A series of open-ended questions was posed to each group of obstetricians; responses were audio recorded and transcribed. Transcriptions were analyzed by two coders using thematic analysis. RESULTS: Four focus groups were convened. Prominent themes included: (1) Obstetrician knowledge about neonatal outcomes is limited, (2) Periviability counseling is both time intensive and time-challenged, (3) Patient processing of information relies on the content, delivery and patient readiness, and (4) Obstetrician bias is toward advocating for maternal safety, which may run counter to parental instinct to "do everything." The last theme was specifically focused on the role of cesarean delivery. CONCLUSIONS: Curricula focused on improving obstetrician periviability counseling should focus on neonatal outcomes, the role of cesarean delivery, and utilization of shared decision-making.

Selective inhibition of MCL1 overcomes venetoclax resistance in a murine model of myelodysplastic syndromes.

Treatment for myelodysplastic syndromes (MDS) remains insufficient due to clonal heterogeneity and lack of effective clinical therapies. Dysregulation of apoptosis is observed across MDS subtypes regardless of mutations and represents an attractive therapeutic opportunity. Venetoclax (VEN), a selective inhibitor of anti-apoptotic protein B-cell lymphoma- 2 (BCL2), has yielded impressive responses in older patients with acute myeloid leukemia (AML) and high risk MDS. BCL2 family anti-apoptotic proteins BCL-XL and induced myeloid cell leukemia 1 (MCL1) are implicated in leukemia survival, and upregulation of MCL1 is seen in VEN-resistant AML and MDS. We determined in vitro sensitivity of MDS patient samples to selective inhibitors of BCL2, BCL-XL and MCL1. While VEN response positively correlated with MDS with excess blasts, all MDS subtypes responded to MCL1 inhibition. Treatment with combined VEN + MCL1 inhibtion was synergistic in all MDS subtypes without significant injury to normal hematopoiesis and reduced MDS engraftment in MISTRG6 mice, supporting the pursuit of clinical trials with combined BCL2 + MCL1 inhibition in MDS.

BET inhibitors reduce cell size and induce reversible cell cycle arrest in AML.

Inhibitors of the bromodomain and extraterminal domain family (BETi) offer a new approach to treat hematological malignancies, with leukemias containing mixed lineage leukemia rearrangements being especially sensitive due to a reliance on the regulation of transcription elongation. We explored the mechanism of action of BETi in cells expressing the t(8;21), and show that these compounds reduced the size of acute myeloid leukemia cells, triggered a rapid but reversible G0 /G1 arrest, and with time, cause cell death. Meta-analysis of PRO-seq data identified ribosomal genes, which are regulated by MYC, were downregulated within 3 hours of addition of the BETi. This reduction of MYC regulated metabolic genes coincided with the loss of mitochondrial respiration and large reductions in the glycolytic rate. In addition, gene expression analysis showed that transcription of BCL2 was rapidly affected by BETi but this did not cause dramatic increases in cell death. Cell cycle arrest, lowered metabolic activity, and reduced BCL2 levels suggested that a second compound was needed to push these cells over the apoptotic threshold. Indeed, low doses of the BCL2 inhibitor, venetoclax, in combination with the BETi was a potent combination in t(8;21) containing cells. Thus, BET inhibitors that affect MYC and BCL2 expression should be considered for combination therapy with venetoclax.

Myeloid translocation gene 16 is required for maintenance of haematopoietic stem cell quiescence.

The t(8;21) and t(16;21) that are associated with acute myeloid leukaemia disrupt two closely related genes termed Myeloid Translocation Genes 8 (MTG8) and 16 (MTG16), respectively. Many of the transcription factors that recruit Mtg16 regulate haematopoietic stem and progenitor cell functions and are required to maintain stem cell self-renewal potential. Accordingly, we found that Mtg16-null bone marrow (BM) failed in BM transplant assays. Moreover, when removed from the animal, Mtg16-deficient stem cells continued to show defects in stem cell self-renewal assays, suggesting a requirement for Mtg16 in this process. Gene expression analysis indicated that Mtg16 was required to suppress the expression of several key cell-cycle regulators including E2F2, and chromatin immunoprecipitation assays detected Mtg16 near an E2A binding site within the first intron of E2F2. BrdU incorporation assays indicated that in the absence of Mtg16 more long-term stem cells were in the S phase, even after competitive BM transplantation where normal stem and progenitor cells are present, suggesting that Mtg16 plays a role in the maintenance of stem cell quiescence.

Nanoparticle STING Agonist Reprograms the Bone Marrow to an Antitumor Phenotype and Protects Against Bone Destruction.

When breast cancer metastasizes to bone, treatment options are limited. Failure to treat bone metastases is thought to be due to therapy-resistant features of the bone marrow microenvironment. Using a murine model of bone metastatic mammary carcinoma, we demonstrate that systemic delivery of polymer nanoparticles loaded with cyclic dinucleotide (CDN) agonists of stimulator of interferon genes (STING) inhibited tumor growth and bone destruction after 7 days of treatment. Each dose of STING-activating nanoparticles trafficked to the bone marrow compartment and was retained within the tumor microenvironment for over 24 hours, enhancing antitumor immunity through proinflammatory cytokine production and early T-cell activation. While acquired resistance mechanisms, including increased levels of immunosuppressive cytokines and the infiltration of regulatory T cells, ultimately limited antitumor efficacy after 2 weeks of treatment, bone protective effects remained. Overall, these studies demonstrate that STING pathway activation, here enabled using a nanomedicine approach to enhance CDN delivery to bone metastatic sites, can reprogram the immune contexture of the bone marrow to an antitumor phenotype that inhibits bone colonization of metastatic breast cancer cells and protects from tumor-mediated bone destruction. Significance: Bone metastases are difficult to treat due to the inaccessibility of the bone marrow compartment and the immunosuppressive microenvironment that protects resident stem cells. Packaging a STING agonist into a nanoparticle that enables systemic administration and drug accumulation at tumor sites overcomes both barriers to stymie metastatic breast cancer growth.

Comparison of blogged and written reflections in two medicine clerkships.

CONTEXT: academic medical centres may adopt new learning technologies with little data on their effectiveness or on how they compare with traditional methodologies. We conducted a comparative study of student reflective writings produced using either an electronic (blog) format or a traditional written (essay) format to assess differences in content, depth of reflection and student preference. METHODS: students in internal medicine clerkships at two US medical schools during the 2008-2009 academic year were quasi-randomly assigned to one of two study arms according to which they were asked to either write a traditional reflective essay and subsequently join in faculty-moderated, small-group discussion (n = 45), or post two writings to a faculty-moderated group blog and provide at least one comment on a peer's posts (n = 50). Examples from a pilot block were used to refine coding methods and determine inter-rater reliability. Writings were coded for theme and level of reflection by two blinded authors; these coding processes reached inter-rater reliabilities of 91% and 80%, respectively. Anonymous pre- and post-clerkship surveys assessed student perceptions and preferences. RESULTS: student writing addressed seven main themes: (i) being humanistic; (ii) professional behaviour; (iii) understanding caregiving relationships; (iv) being a student; (v) clinical learning; (vi) dealing with death and dying, and (vii) the health care system, quality, safety and public health. The distribution of themes was similar across institutions and study arms. The level of reflection did not differ between study arms. Post-clerkship surveys showed that student preferences for blogging or essay writing were predicted by experience, with the majority favouring the method they had used. CONCLUSIONS: our study suggests there is no significant difference in themes addressed or levels of reflection achieved when students complete a similar assignment via online blogging or traditional essay writing. Given this, faculty staff should feel comfortable in utilising the blog format for reflective exercises. Faculty members could consider the option of using either format to address different learning styles of students.

The delta isoform of phosphatidylinositol-3-kinase predominates in chronic myelomonocytic leukemia and can be targeted effectively with umbralisib and ruxolitinib.

Chronic myelomonocytic leukemia (CMML) is a myelodysplastic syndrome/myeloproliferative neoplasm overlap syndrome characterized by monocytic proliferation in the presence of dysplastic bone marrow changes, inflammatory symptoms, and propensity for transformation to acute myeloid leukemia (AML), with a poor prognosis and limited treatment options. Unlike the α and ß isoforms, the phosphatidylinositol-3-kinase (PI3K)-δ signaling protein is predominantly expressed by hematopoietic cells and therefore has garnered interest as a potential target for the treatment of lymphomas and leukemias. We revealed a pattern of increased PIK3CD:PIK3CA ratio in monocytic M5 AML patients and cell lines, and this ratio correlated with responsiveness to pharmacological PI3K-δ inhibition in vitro. Because CMML is a disease defined by monocytic clonal proliferation, we tested the PI3K-δ inhibitor umbralisib as a single agent and in combination with the JAK1/2 inhibitor ruxolitinib, in CMML. Our ex vivo experiments with primary CMML patient samples revealed synergistic inhibition of viability and clonogenicity with this combination. Phospho-specific flow cytometry revealed that dual inhibition had the unique ability to decrease STAT5, ERK, AKT, and S6 phosphorylation simultaneously, which offers a mechanistic hypothesis for the enhanced efficacy of the combination treatment. These preclinical data indicate promising activity by co-inhibition of PI3K-δ and JAK1/2 and support the use of ruxolitinib + umbralisib combination therapy in CMML under active clinical investigation.

BET Inhibition Enhances the Antileukemic Activity of Low-dose Venetoclax in Acute Myeloid Leukemia.

PURPOSE: The BCL2 inhibitor, venetoclax, has transformed clinical care in acute myeloid leukemia (AML). However, subsets of patients do not respond or eventually acquire resistance. Venetoclax-based regimens can lead to considerable marrow suppression in some patients. Bromodomain and extraterminal inhibitors (BETi) are potential treatments for AML, as regulators of critical AML oncogenes. We tested the efficacy of novel BET inhibitor INCB054329, and its synergy with venetoclax to reduce AML without induction of hematopoietic toxicity. EXPERIMENTAL DESIGN: INCB054329 efficacy was assessed by changes in cell cycle and apoptosis in treated AML cell lines. In vivo efficacy was assessed by tumor reduction in MV-4-11 cell line-derived xenografts. Precision run-on and sequencing (PRO-seq) evaluated effects of INCB054329. Synergy between low-dose BETi and venetoclax was assessed in cell lines and patient samples in vitro and in vivo while efficacy and toxicity was assessed in patient-derived xenograft (PDX) models. RESULTS: INCB054329 induced dose-dependent apoptosis and quiescence in AML cell lines. PRO-seq analysis evaluated the effects of INCB054329 on transcription and confirmed reduced transcriptional elongation of key oncogenes, MYC and BCL2, and genes involved in the cell cycle and metabolism. Combinations of BETi and venetoclax led to reduced cell viability in cell lines and patient samples. Low-dose combinations of INCB054329 and venetoclax in cell line and PDX models reduced AML burden, regardless of the sensitivity to monotherapy without development of toxicity. CONCLUSIONS: Our findings suggest low dose combinations of venetoclax and BETi may be more efficacious for patients with AML than either monotherapy, potentially providing a longer, more tolerable dosing regimen.

Selective Inhibition of JAK1 Primes STAT5-Driven Human Leukemia Cells for ATRA-Induced Differentiation.

BACKGROUND: All-trans retinoic acid (ATRA), a derivate of vitamin A, has been successfully used as a therapy to induce differentiation in M3 acute promyelocytic leukemia (APML), and has led to marked improvement in outcomes. Previously, attempts to use ATRA in non-APML in the clinic, however, have been underwhelming, likely due to persistent signaling through other oncogenic drivers. Dysregulated JAK/STAT signaling is known to drive several hematologic malignancies, and targeting JAK1 and JAK2 with the JAK1/JAK2 inhibitor ruxolitinib has led to improvement in survival in primary myelofibrosis and alleviation of vasomotor symptoms and splenomegaly in polycythemia vera and myelofibrosis. OBJECTIVE: While dose-dependent anemia and thrombocytopenia limit the use of JAK2 inhibition, selectively targeting JAK1 has been explored as a means to suppress inflammation and STAT-associated pathologies related to neoplastogenesis. The objective of this study is to employ JAK1 inhibition (JAK1i) in the presence of ATRA as a potential therapy in non-M3 acute myeloid leukemia (AML). METHODS: Efficacy of JAK1i using INCB52793 was assessed by changes in cell cycle and apoptosis in treated AML cell lines. Transcriptomic and proteomic analysis evaluated effects of JAK1i. Synergy between JAK1i+ ATRA was assessed in cell lines in vitro while efficacy in vivo was assessed by tumor reduction in MV-4-11 cell line-derived xenografts. RESULTS: Here we describe novel synergistic activity between JAK1i inhibition and ATRA in non-M3 leukemia. Transcriptomic and proteomic analysis confirmed structural and functional changes related to maturation while in vivo combinatory studies revealed significant decreases in leukemic expansion. CONCLUSIONS: JAK1i+ ATRA lead to decreases in cell cycle followed by myeloid differentiation and cell death in human leukemias. These findings highlight potential uses of ATRA-based differentiation therapy of non-M3 human leukemia.

Accelerated Graduation and the Deployment of New Physicians During the COVID-19 Pandemic.

The COVID-19 pandemic has presented unprecedented challenges and opportunities for medical schools in the United States. In this Invited Commentary, the authors describe a unique collaboration between the University of Massachusetts Medical School (UMMS), the only public medical school in the state; the University of Massachusetts Memorial Medical Center (UMMMC); and the Commonwealth of Massachusetts. Through this partnership, UMMS was able to graduate fourth-year medical students 2 months early and deploy them to UMMMC to care for patients and alleviate workforce shortages during the COVID-19 surge, which peaked in Massachusetts in April 2020. The authors describe how they determined if students had fulfilled graduation requirements to graduate early, what commencement and the accompanying awards ceremony looked like this year as virtual events, the special emergency 90-day limited license these new graduates were given to practice at UMMMC during this time, and the impact these new physicians had in the hospital allowing residents and attendings to be redeployed to care for COVID-19 patients.

Design, analysis, power, and sample size calculation for three-phase interrupted time series analysis in evaluation of health policy interventions.

OBJECTIVE: To discuss the study design and data analysis for three-phase interrupted time series (ITS) studies to evaluate the impact of health policy, systems, or environmental interventions. Simulation methods are used to conduct power and sample size calculation for these studies. METHODS: We consider the design and analysis of three-phase ITS studies using a study funded by National Institutes of Health as an exemplar. The design and analysis of both one-arm and two-arm three-phase ITS studies are introduced. RESULTS: A simulation-based approach, with ready-to-use computer programs, was developed to determine the power for two types of three-phase ITS studies. Simulations were conducted to estimate the power of segmented autoregressive (AR) error models when autocorrelation ranged from -0.9 to 0.9 with various effect sizes. The power increased as the sample size or the effect size increased. The power to detect the same effect sizes varied largely, depending on testing level change, trend changes, or both. CONCLUSION: This article provides a convenient tool for investigators to generate sample sizes to ensure sufficient statistical power when three-phase ITS study design is implemented.

Simulation-based power and sample size calculation for designing interrupted time series analyses of count outcomes in evaluation of health policy interventions.

OBJECTIVE: The purpose of this study was to present the design, model, and data analysis of an interrupted time series (ITS) model applied to evaluate the impact of health policy, systems, or environmental interventions using count outcomes. Simulation methods were used to conduct power and sample size calculations for these studies. METHODS: We proposed the models and analyses of ITS designs for count outcomes using the Strengthening Translational Research in Diverse Enrollment (STRIDE) study as an example. The models we used were observation-driven models, which bundle a lagged term on the conditional mean of the outcome for a time series of count outcomes. RESULTS: A simulation-based approach with ready-to-use computer programs was developed to calculate the sample size and power of two types of ITS models, Poisson and negative binomial, for count outcomes. Simulations were conducted to estimate the power of segmented autoregressive (AR) error models when autocorrelation ranged from -0.9 to 0.9, with various effect sizes. The power to detect the same magnitude of parameters varied largely, depending on the testing level change, the trend change, or both. The relationships between power and sample size and the values of the parameters were different between the two models. CONCLUSION: This article provides a convenient tool to allow investigators to generate sample sizes that will ensure sufficient statistical power when the ITS study design of count outcomes is implemented.

A REDCap-based model for electronic consent (eConsent): Moving toward a more personalized consent.

INTRODUCTION: The updated common rule, for human subjects research, requires that consents "begin with a 'concise and focused' presentation of the key information that will most likely help someone make a decision about whether to participate in a study" (Menikoff, Kaneshiro, Pritchard. The New England Journal of Medicine. 2017; 376(7): 613-615.). We utilized a community-engaged technology development approach to inform feature options within the REDCap software platform centered around collection and storage of electronic consent (eConsent) to address issues of transparency, clinical trial efficiency, and regulatory compliance for informed consent (Harris, et al. Journal of Biomedical Informatics 2009; 42(2): 377-381.). eConsent may also improve recruitment and retention in clinical research studies by addressing: (1) barriers for accessing rural populations by facilitating remote consent and (2) cultural and literacy barriers by including optional explanatory material (e.g., defining terms by hovering over them with the cursor) or the choice of displaying different videos/images based on participant's race, ethnicity, or educational level (Phillippi, et al. Journal of Obstetric, Gynecologic, & Neonatal Nursing. 2018; 47(4): 529-534.). METHODS: We developed and pilot tested our eConsent framework to provide a personalized consent experience whereby users are guided through a consent document that utilizes avatars, contextual glossary information supplements, and videos, to facilitate communication of information. RESULTS: The eConsent framework includes a portfolio of eight features, reviewed by community stakeholders, and tested at two academic medical centers. CONCLUSIONS: Early adoption and utilization of this eConsent framework have demonstrated acceptability. Next steps will emphasize testing efficacy of features to improve participant engagement with the consent process.

Venetoclax response is enhanced by selective inhibitor of nuclear export compounds in hematologic malignancies.

The selective inhibitor of nuclear export (SINE) compounds selinexor (KPT-330) and eltanexor (KPT-8602) are from a novel class of small molecules that target exportin-1 (XPO1 [CRM1]), an essential nucleo-cytoplasmic transport protein responsible for the nuclear export of major tumor suppressor proteins and growth regulators such as p53, p21, and p27. XPO1 also affects the translation of messenger RNAs for critical oncogenes, including MYC, BCL2, MCL1, and BCL6, by blocking the export of the translation initiation factor eIF4E. Early trials with venetoclax (ABT-199), a potent, selective inhibitor of BCL2, have revealed responses across a variety of hematologic malignancies. However, many tumors are not responsive to venetoclax. We used models of acute myeloid leukemia (AML) and diffuse large B-cell lymphoma (DLBCL) to determine in vitro and in vivo responses to treatment with venetoclax and SINE compounds combined. Cotreatment with venetoclax and SINE compounds demonstrated loss of viability in multiple cell lines. Further in vitro analyses showed that this enhanced cell death was the result of an increase in apoptosis that led to a loss of clonogenicity in methylcellulose assays, coinciding with activation of p53 and loss of MCL1. Treatment with SINE compounds and venetoclax combined led to a reduction in tumor growth in both AML and DLBCL xenografts. Immunohistochemical analysis of tissue sections revealed that the reduction in tumor cells was partly the result of an induction of apoptosis. The enhanced effects of this combination were validated in primary AML and DLBCL patient cells. Our studies reveal synergy with SINE compounds and venetoclax in aggressive hematologic malignancies and provide a rationale for pursuing this approach in a clinical trial.

Prescribers and pharmaceutical representatives: why are we still meeting?

CONTEXT: Research suggests that pharmaceutical marketing influences prescribing and may cause cognitive dissonance for prescribers. This work has primarily been with physicians and physician-trainees. Questions remain regarding why prescribers continue to meet with pharmaceutical representatives (PRs). OBJECTIVE: To describe the reasons that prescribers from various health professions continue to interact with PRs despite growing evidence of the influence of these interactions. DESIGN, SETTING, AND PARTICIPANTS: Multi-disciplinary focus groups with 61 participants held in practice settings and at society meetings. RESULTS: Most prescribers participating in our focus groups believe that overall PR interactions are beneficial to patient care and practice health. They either trust the information from PRs or feel that they are equipped to evaluate it independently. Despite acknowledgement of study findings to the contrary, prescribers state that they are able to effectively manage PR interactions such that their own prescribing is not adversely impacted. Prescribers describe few specific strategies or policies for these interactions, and report that policies are not consistently implemented with all members of a clinic or institution. Some prescribers perceive an inherent contradiction between academic centers and national societies receiving money from pharmaceutical companies, and then recommending restriction at the level of the individual prescriber. Prescribers with different training backgrounds present a few novel reasons for these meetings. CONCLUSIONS: Despite evidence that PR detailing influences prescribing, providers from several health professions continue to believe that PR interactions improve patient care, and that they can adequately evaluate and filter information presented to them by PRs. Focus group comments suggest that cultural change is necessary to break the norms that exist in many settings. Applying policies consistently, considering non-physician members of the healthcare team, working with trainees, restructuring the current primary care model and offering convenient, individualized, non-biased educational options may aid success.

Preparing Medical Students to Be Physician Leaders: A Leadership Training Program for Students Designed and Led by Students.

Introduction: Leadership is an area of education and training that is critical to the development of medical providers as health care professionals, yet few medical school curricula offer formal training in this area. Methods: We designed and implemented a course to develop and enhance the leadership and teamwork skills of first-year medical students to better prepare them for medical practice. Following a systematic literature review to identify leadership core competencies, the Leadership in Medicine Optional Enrichment Elective (OEE) was developed in accordance with the University of Massachusetts Medical School's course guidelines. The elective included six interactive sessions to advance skills in the areas of recognizing and utilizing effective leadership styles, communication within the health care team, giving and receiving feedback, delegating responsibilities, and direction setting. We designed a robust, evidence-based, scholarly evaluation plan for the OEE that was integral to ongoing quality improvement of the course. Results: Outcomes were assessed in alignment with the Kirkpatrick method of standardized evaluation. A total of 26 participants completed the course. At completion, participants demonstrated learning and advancement of skills in all five leadership domains. Furthermore, participants found meaning in the course and planned to utilize their skills in future medical practice. Discussion: The development, implementation, and evaluation of this program can serve as a model for future course development, and the program can be adapted and implemented by other institutions in an effort to address the learning gap regarding leadership education.

Between two worlds: a multi-institutional qualitative analysis of students' reflections on joining the medical profession.

BACKGROUND: Recent changes in healthcare system and training mandates have altered the clinical learning environment. We incorporated reflective writing into Internal Medicine clerkships (IMcs) in multiple institutions so students could consider the impact of clerkship experiences on their personal and professional development. We analyzed student reflections to inform curricula and support learning. METHODS: We qualitatively analyzed the reflections of students at 3 US medical schools during IMcs (N = 292) to identify themes, tone, and reflective quality using an iterative approach. Chi-square tests assessed differences between these factors and across institutions. FINDINGS: Students openly described powerful experiences. Major themes focused on 4 categories: personal issues (PI), professional development (PD), relational issues (RI), and medical care (MC). Each major theme was represented at each institution, although with significant variability between institutions in many of the subcategories including student role (PI), development-as-a-physician (PD), professionalism (PD) (p < 0.001). Students used positive tones to describe student role, development-as-a-physician and physician-patient relationship (PD) (p < 0.01-0.001), and negative tones for quality and safety (MC) (p < 0.05). Only 4% of writings coded as professionalism had a positive tone. Students employed a "reporting" voice in writing about clinical problem-solving, healthcare systems, and quality/safety (MC). DISCUSSION: Reflection is considered important to professional development. Our analysis suggests that students at 3 institutions reflect on similar experiences. Theme variability across institutions implies curricula should be tailored to local culture. Reflective quality analysis suggests students are better equipped to reflect on certain experiences over others, which may impact learning. Student reflections can function as a mirror for our organizations, offer institutional feedback for support and improvement, and inform curricula for learners and faculty.

A Novel MCL1 Inhibitor Combined with Venetoclax Rescues Venetoclax-Resistant Acute Myelogenous Leukemia.

Suppression of apoptosis by expression of antiapoptotic BCL2 family members is a hallmark of acute myeloblastic leukemia (AML). Induced myeloid leukemia cell differentiation protein (MCL1), an antiapoptotic BCL2 family member, is commonly upregulated in AML cells and is often a primary mode of resistance to treatment with the BCL2 inhibitor venetoclax. Here, we describe VU661013, a novel, potent, selective MCL1 inhibitor that destabilizes BIM/MCL1 association, leads to apoptosis in AML, and is active in venetoclax-resistant cells and patient-derived xenografts. In addition, VU661013 was safely combined with venetoclax for synergy in murine models of AML. Importantly, BH3 profiling of patient samples and drug-sensitivity testing ex vivo accurately predicted cellular responses to selective inhibitors of MCL1 or BCL2 and showed benefit of the combination. Taken together, these data suggest a strategy of rationally using BCL2 and MCL1 inhibitors in sequence or in combination in AML clinical trials. SIGNIFICANCE: Targeting antiapoptotic proteins in AML is a key therapeutic strategy, and MCL1 is a critical antiapoptotic oncoprotein. Armed with novel MCL1 inhibitors and the potent BCL2 inhibitor venetoclax, it may be possible to selectively induce apoptosis by combining or thoughtfully sequencing these inhibitors based on a rational evaluation of AML.See related commentary by Leber et al., p. 1511.This article is highlighted in the In This Issue feature, p. 1494.

MTG16 is a tumor suppressor in colitis-associated carcinoma.

MTG16 is a member of the myeloid translocation gene (MTG) family of transcriptional corepressors. While MTGs were originally identified in chromosomal translocations in acute myeloid leukemia, recent studies have uncovered a role in intestinal biology. For example, Mtg16-/- mice have increased intestinal proliferation and are more sensitive to intestinal injury in colitis models. MTG16 is also underexpressed in patients with moderate/severe ulcerative colitis. Based on these findings, we postulated that MTG16 might protect against colitis-associated carcinogenesis. MTG16 was downregulated at the protein and RNA levels in patients with inflammatory bowel disease and in those with colitis-associated carcinoma. Mtg16-/- mice subjected to inflammatory carcinogenesis modeling exhibited worse colitis and increased tumor multiplicity and size. Loss of MTG16 also increased severity of dysplasia, apoptosis, proliferation, DNA damage, and WNT signaling. Moreover, transplantation of WT marrow into Mtg16-/- mice failed to rescue the Mtg16-/- protumorigenic phenotypes, indicating an epithelium-specific role for MTG16. While MTG dysfunction is widely appreciated in hematopoietic malignancies, the role of this gene family in epithelial homeostasis, and in colon cancer, was unrealized. This report identifies MTG16 as an important modulator of colitis and tumor development in inflammatory carcinogenesis.

Discovery and biological characterization of potent myeloid cell leukemia-1 inhibitors.

Myeloid cell leukemia 1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family of proteins that when overexpressed is associated with high tumor grade, poor survival, and resistance to chemotherapy. Mcl-1 is amplified in many human cancers, and knockdown of Mcl-1 using RNAi can lead to apoptosis. Thus, Mcl-1 is a promising cancer target. Here, we describe the discovery of picomolar Mcl-1 inhibitors that cause caspase activation, mitochondrial depolarization, and selective growth inhibition. These compounds represent valuable tools to study the role of Mcl-1 in cancer and serve as useful starting points for the discovery of clinically useful Mcl-1 inhibitors. PDB ID CODES: Comp. 2: 5IEZ; Comp. 5: 5IF4.