Supplemental Figure S3. Relative expression of Ebp1 and rRNA synthesis in bone marrow cells from control and MLL-AF9 and MLL-AF10 mice.

Primer sequences for GCLC, GCLM, NQO1, NRF2 and GAPDH analysis by real-time RT-PCR analysis.

Supplemental Figure S1. Relative expression of Ebp1 in primary AML cells as compared to normal mononuclear cells.

Patient characteristics and molecular phenotypes of primary AML samples used.

Evaluation of induction of (A) reactive oxygen species, (B) hydrogen peroxide (H2O2), and of the N-acetylcysteine (NAC) pre-treatment effect on ixazomib-induced (C) superoxide and (D) apoptosis in OCI-AML3 cells.

In vivo analysis of patients AML1-3 including (A) H2O2 levels, (B) WBC counts of AML3 during ixazomib treatment (arrow marks when hydrea stopped), and (C) mRNA expression (AML2).

Effects of combining ixazomib and Trichostatin A (TSA) (A, B, C), and of combining bortezomib and SAHA (D, E) in OCI-AML3 cells with or without depletion of NPMc+ expression.

(A) GSH to GSSG ratio, (B) reduced GSH, and (C) oxidized glutathione (GSSG) in OCI-AML3 cells (ixazomib 150nM, 22h treatment).

(A) Representative FACS plot of sorted NPMc+ primary leukemic blasts (patient AML6) and (B) mRNA expression by qPCR using the same AML patient samples tested in Figure 4.

Supplemental Figure S2. Effects of Ebp1 depletion on cell proliferation in K562 leukemic cells.

Supplemental Figure S5. Colocalization of Ebp1 p48 and Pol I complex.

Supplemental data contains supplemental figure legends, supplemental tables and supplemental materials and methods. Supplemental Table 1. Target sequences of siRNAs Supplemental Table 2. Primer's sequences for RT-qPCR Supplemental Table S3: Patient characteristics

(A) Cytotoxicity of ixazomib compared to MLN2238 (IC50 = 63.68 {plus minus} 5.3 nM) in OCI-AML3 cells. Plots of (B) GFP expression by K562 cells ectopically expressing constructs (C) treated with ixazomib.

Abstract Background: The human papillomavirus (HPV) virus is a known pathogen and carcinogen causing deadly cancers of the genitalia and head and neck. The HPV vaccine is a safe, effective cancer-preventing vaccine recommended for girls and boys at ages 11-12. Full HPV vaccine coverage is available through health insurance plans and the state of California, yet no data were readily available to describe California state-wide coverage of HPV vaccination. The Data Workgroup of the California HPV Vaccination Roundtable aimed to map State-level HPV vaccine coverage. Methods: Workgroup collected, analyzed, and mapped 2018 HPV vaccination data from the NIS-T survey, quality performance metrics from public and private health plans, and the statewide CAIR. NIS-T provides state-level estimates of routine adolescent vaccines, including HPV. Performance data were obtained from Medi-Cal and commercial health plans, administrative claims, and medical records. CAIR contains individual-level, provider-reported immunizations. HPV vaccination coverage for adolescents were estimated at the state and county level. Maps of county-level HPV vaccination and HPV-related cancer rates were built. Results: Rates of HPV-related cancers ranged from 6-12 per 100,000. Regarding HPV vaccination, there were considerable variation in the metrics and limitations of each data source, therefore estimates are not easily comparable. CAIR estimates of HPV vaccination coverage (28%) are lower than those for Medi-Cal managed care (45%) and commercial HMO members (50%). In 2018, aggregated results showed that overall 50% of 13 year old were vaccinated. We observed in the CAIR data that boys and girls are vaccinated at similar rates. However, significant county/regional HPV vaccination rates exist ranging from 9% (rural, northern) to 55% (urban, western). Northern, rural country have both the lowest HPV vaccination completion rates for 13-year-olds (9%), and the highest HPV-attributable cancer rates in the state (12 cases per 100,000 persons. Race/ethnic variations exist for HPV vaccination and HPV- related cancers–especially cervical cancer. Conclusions: This state-level data report approach may facilitate practice and policy action and help other states in developing their own reports for HPV vaccine improvements. Stakeholders are encouraged to utilize this Report when planning HPV vaccination interventions. We recommend that health systems: 1) assess HPV vaccination rates for 13-year-olds, 2) establish data exchange with CAIR, 3) implement recommended strategies to improve coverage, 4) collaborate with health plans and clinicians and 5) partner with community advocacy groups and clinic/hospital parent/patient advisory groups to improve data accuracy, as well as reduce HPV vaccine hesitance and promote at least 80% HPV vaccination completion by 2026. Citation Format: Jaime Adler, Raquel Arias, Kimlin Tam Ashing, Shauntay Davis-Patterson, Hilary Gillette-Walch, Jeffrey Klausner, Jim Knox, Beverly Mitchell, Autumn Ogden-Smith, Jane Pezua, Rita Singhal, Hoa Su. Human papillomavirus vaccination: California state-level mapping to identify gaps and inform practice and policy [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-273.

This article comments on an innovative case study in Consulting Psychology Journal: Practice and Research titled "Transformation to Academic Leadership: The Role of Mentorship and Executive Coaching" by W. Kimryn Rathmell, Nancy J. Brown, and Richard R. Kilburg. The case study documents the development of a physician scientist who takes on an important leadership role. Drawing on my background in leadership positions at 3 very different institutions of academic medical research, I discuss the tremendous importance of effective leadership to those institutions as well as the foundational roles of experience and persistence in leadership development in such an environment. In the absence of professional coaching, I have been able to develop my leadership skills through trial and error with the help of some excellent mentors. Although experience and personal capabilities are important, I note that the role of a coach can greatly facilitate the process of learning to lead, alleviating much of the travail that frequently accompanies the transition to new leadership positions. In addition, I point out the value of extending leadership training to more junior faculty as an approach to increasing the talent pool from which to choose the next generation of leaders.

We have recently reported that activation of Brd4 is associated with the presence of autophagy in NPMc+ and MLL AML cells. In order to determine the mechanisms underlying this relationship, we have examined the role of Brd4 in regulating the expression of several genes that are central to the process of autophagy. We found that Brd4 binds to the promoters of ATG 3, 7 and CEBPβ, and expression of these genes is markedly reduced by inhibitors of Brd4, as well as by Brd4-shRNA and depletion of CEBPβ. Inhibitors of Brd4 also dramatically suppress the transcription of Keap1, thereby increasing the expression of anti-oxidant genes through the Nrf2 pathway and reducing the cytotoxicity induced by Brd4 inhibitors. Elimination of ATG3 or KEAP1 expression using CRISPR-cas9 mediated genomic editing markedly reduced autophagy. We conclude that Brd4 plays a significant role in autophagy activation through the direct transcriptional regulation of genes essential for it, as well as through the Keap1-Nrf2 axis in NPMc+ and MLL-fusion AML cells.

We are in the midst of a technological revolution that is providing new insights into human biology and cancer. In this era of big data, we are amassing large amounts of information that is transforming how we approach cancer treatment and prevention. Enactment of the Cancer Moonshot within the 21st Century Cures Act in the USA arrived at a propitious moment in the advancement of knowledge, providing nearly US$2 billion of funding for cancer research and precision medicine. In 2016, the Blue Ribbon Panel (BRP) set out a roadmap of recommendations designed to exploit new advances in cancer diagnosis, prevention, and treatment. Those recommendations provided a high-level view of how to accelerate the conversion of new scientific discoveries into effective treatments and prevention for cancer. The US National Cancer Institute is already implementing some of those recommendations. As experts in the priority areas identified by the BRP, we bolster those recommendations to implement this important scientific roadmap. In this Commission, we examine the BRP recommendations in greater detail and expand the discussion to include additional priority areas, including surgical oncology, radiation oncology, imaging, health systems and health disparities, regulation and financing, population science, and oncopolicy. We prioritise areas of research in the USA that we believe would accelerate efforts to benefit patients with cancer. Finally, we hope the recommendations in this report will facilitate new international collaborations to further enhance global efforts in cancer control.

The mechanisms underlying activation of the BET pathway in AML cells remain poorly understood. We have discovered that autophagy is activated in acute leukemia cells expressing mutant nucleophosmin 1 (NPMc+) or MLL-fusion proteins. Autophagy activation results in the degradation of NPM1 and HEXIM1, two negative regulators of BET pathway activation. Inhibition of autophagy with pharmacologic inhibitors or through knocking down autophagy-related gene 5 (Atg5) expression increases the expression of both NPM1 and HEXIM1. The Brd4 inhibitors JQ1 and I-BET-151 also inhibit autophagy and increase NPM1 and HEXIM1 expression. We conclude that the degradation of NPM1 and HEXIM1 through autophagy in certain AML subsets contributes to the activation of the BET pathway in these cells.

Abstract Purpose: The ErbB3-binding protein 1 (Ebp1) has been implicated in diverse cancers as having either oncogenic or tumor suppressor activities. The present study was undertaken to determine the effects of Ebp1 expression in AML cells and to determine the mechanisms by which Ebp1 promotes cell proliferation in these cells. Experimental Design: The expression of Ebp1 was studied in mononuclear cells obtained from the peripheral blood of 54 patients with AML by Western blot analysis. The effects of Ebp1 expression on proliferating cell nuclear antigen (PCNA) expression and cell proliferation was measured using Western blot analysis, immunoprecipitation, in vitro ubiquitination, and colony-forming assays. The role of Ebp1 in promoting rRNA synthesis and cell proliferation was evaluated by measuring the level of pre-rRNA and the recruitment of Pol I to rDNA. Results: Ebp1 is highly expressed in acute myelogenous leukemia (AML) cells and regulates the level of ribosomal RNA (rRNA) synthesis by binding to RNA Polymerase I (Pol I) and enhancing the formation of the Pol I initiation complex. Ebp1 also increases the stability of PCNA protein by preventing its interaction with Mdm2, for which it is a substrate. Conclusions: These results demonstrate an important role of Ebp1 in promoting cell proliferation in AML cells through the regulation of both rRNA synthesis and PCNA expression. Clin Cancer Res; 22(13); 3320–7. ©2016 AACR.