FOXA1 Mutations Reveal Distinct Chromatin Profiles and Influence Therapeutic Response in Breast Cancer.

Mutations in the pioneer transcription factor FOXA1 are a hallmark of estrogen receptor-positive (ER) breast cancers. Examining FOXA1 in ∼5,000 breast cancer patients identifies several hotspot mutations in the Wing2 region and a breast cancer-specific mutation SY242CS, located in the third β strand. Using a clinico-genomically curated cohort, together with breast cancer models, we find that FOXA1 mutations associate with a lower response to aromatase inhibitors.

Therapeutic targeting of 15-PGDH in murine pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by interstitial remodeling and pulmonary dysfunction. The etiology of IPF is not completely understood but involves pathologic inflammation and subsequent failure to resolve fibrosis in response to epithelial injury. Treatments for IPF are limited to anti-inflammatory and immunomodulatory agents, which are only partially effective.

ARID1A determines luminal identity and therapeutic response in estrogen-receptor-positive breast cancer.

Mutations in ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, are the most common alterations of the SWI/SNF complex in estrogen-receptor-positive (ER) breast cancer. We identify that ARID1A inactivating mutations are present at a high frequency in advanced endocrine-resistant ER breast cancer. An epigenome CRISPR-CAS9 knockout (KO) screen identifies ARID1A as the top candidate whose loss determines resistance to the ER degrader fulvestrant.

ID1 Mediates Escape from TGFβ Tumor Suppression in Pancreatic Cancer.

TGFβ is an important tumor suppressor in pancreatic ductal adenocarcinoma (PDA), yet inactivation of TGFβ pathway components occurs in only half of PDA cases. TGFβ cooperates with oncogenic RAS signaling to trigger epithelial-to-mesenchymal transition (EMT) in premalignant pancreatic epithelial progenitors, which is coupled to apoptosis owing to an imbalance of SOX4 and KLF5 transcription factors. We report that PDAs that develop with the TGFβ pathway intact avert this apoptotic effect via ID1.

Cohesin Members Stag1 and Stag2 Display Distinct Roles in Chromatin Accessibility and Topological Control of HSC Self-Renewal and Differentiation.

Transcriptional regulators, including the cohesin complex member STAG2, are recurrently mutated in cancer. The role of STAG2 in gene regulation, hematopoiesis, and tumor suppression remains unresolved. We show that Stag2 deletion in hematopoietic stem and progenitor cells (HSPCs) results in altered hematopoietic function, increased self-renewal, and impaired differentiation.

Genome-scale screens identify JNK-JUN signaling as a barrier for pluripotency exit and endoderm differentiation.

Human embryonic stem cells (ESCs) and human induced pluripotent stem cells hold great promise for cell-based therapies and drug discovery. However, homogeneous differentiation remains a major challenge, highlighting the need for understanding developmental mechanisms. We performed genome-scale CRISPR screens to uncover regulators of definitive endoderm (DE) differentiation, which unexpectedly uncovered five Jun N-terminal kinase (JNK)-JUN family genes as key barriers of DE differentiation.

IKZF2 Drives Leukemia Stem Cell Self-Renewal and Inhibits Myeloid Differentiation.

Leukemias exhibit a dysregulated developmental program mediated through both genetic and epigenetic mechanisms. Although IKZF2 is expressed in hematopoietic stem cells (HSCs), we found that it is dispensable for mouse and human HSC function. In contrast to its role as a tumor suppressor in hypodiploid B-acute lymphoblastic leukemia, we found that IKZF2 is required for myeloid leukemia.

HOXA9 Reprograms the Enhancer Landscape to Promote Leukemogenesis.

Aberrant expression of HOXA9 is a prominent feature of acute leukemia driven by diverse oncogenes. Here we show that HOXA9 overexpression in myeloid and B progenitor cells leads to significant enhancer reorganizations with prominent emergence of leukemia-specific de novo enhancers. Alterations in the enhancer landscape lead to activation of an ectopic embryonic gene program.

LSD1 inhibition exerts its antileukemic effect by recommissioning PU.1- and C/EBPα-dependent enhancers in AML.

Epigenetic regulators are recurrently mutated and aberrantly expressed in acute myeloid leukemia (AML). Targeted therapies designed to inhibit these chromatin-modifying enzymes, such as the histone demethylase lysine-specific demethylase 1 (LSD1) and the histone methyltransferase DOT1L, have been developed as novel treatment modalities for these often refractory diseases. A common feature of many of these targeted agents is their ability to induce myeloid differentiation, suggesting that multiple paths toward a myeloid gene expression program can be engaged to relieve the differentiation blockade that is uniformly seen in AML.

Dual Targeting of Oncogenic Activation and Inflammatory Signaling Increases Therapeutic Efficacy in Myeloproliferative Neoplasms.

Genetic and functional studies underscore the central role of JAK/STAT signaling in myeloproliferative neoplasms (MPNs). However, the mechanisms that mediate transformation in MPNs are not fully delineated, and clinically utilized JAK inhibitors have limited ability to reduce disease burden or reverse myelofibrosis. Here we show that MPN progenitor cells are characterized by marked alterations in gene regulation through differential enhancer utilization, and identify nuclear factor κB (NF-κB) signaling as a key pathway activated in malignant and non-malignant cells in MPN.

Selective Inhibition of HDAC1 and HDAC2 as a Potential Therapeutic Option for B-ALL.

Purpose: Histone deacetylase inhibitors (HDACi) have recently emerged as efficacious therapies that target epigenetic mechanisms in hematologic malignancies. One such hematologic malignancy, B-cell acute lymphoblastic leukemia (B-ALL), may be highly dependent on epigenetic regulation for leukemia development and maintenance, and thus sensitive to small-molecule inhibitors that target epigenetic mechanisms.

Experimental Design: A panel of B-ALL cell lines was tested for sensitivity to HDACi with varying isoform sensitivity.

Trends in state and county mental hospitals in the U.S. from 1970 to 1992.

Objective: The authors document changes in state mental hospitals from 1970 to 1992 in four areas: the number of hospitals, the average daily census, expenditures, and number of full-time-equivalent staff.

Methods: Data examined were derived from information collected in the Inventory of Mental Health Organizations and General Hospital Mental Health Services.

Results: From 1970 to 1992, the number of state hospitals dropped from 310 to 273, and their inpatient populations were drastically reduced (a 77 percent decrease), a continuation of a trend that began in 1956.

CMHS data highlights on: availability of psychiatric beds, United States: selected years, 1970-1990.

Despite the decrease from 474,190 to 250,541 between 1970 and 1990 in the overall number of non-Federal psychiatric beds (excluding "scatter" beds in non-Federal general hospitals), the trend was by no means constant over time. Between 1970 and 1982, a period of rapid deinstitutionalization of State mental hospitals, the number of beds in all organizations combined dropped precipitously from 474,190 to 222,666, led by State mental hospitals which decreased from 413,066 to 140,140 beds. This was the height of the community mental health center movement and the prevailing view of mental health administrators was that persons with mental illness could be cared for better in the community, rather than at State mental hospitals, far from their homes.

The effect of inflation on expenditures by mental health organization between 1969 and 1990.

At first glance, the rise in current dollar expenditures for all mental health organizations from $3.3 billion in 1969 to $28.4 billion in 1990 seems enormous.

Persons with substance use disorders in mental health organizations in the United States in 1988.

Data from a 1988 enumeration of mental health organizations and separate psychiatric services of non-Federal general hospitals in the United States were used to derive estimates of the number of person with alcohol and/or drug abuse (substance use) disorders in these organizations. For all organizations combined, the percent of persons with substance use disorders were 8% each in inpatient, residential treatment, and outpatient care and only 3% in partial care program elements. However, within type of program element, there was variation according to type of organization.

Staffing of mental health organizations, United States, 1988.

Between 1986 and 1988, the number of full-time equivalent (FTE) staff employed in specialty mental health organizations in the United States increased 7 percent, from 494,515 to 531,067. Much of this increase could probably be attributed to the increase in number of mental health organizations during this period, from 4,747 to 4,930. With the exception of State mental hospitals and VA psychiatric organizations, all of the other types of mental health organizations showed varying amounts of increase in FTE staff with the most notable gains being reported by private psychiatric hospitals, residential treatment centers for emotionally disturbed children, and multiservice mental health organizations.

Fertility following excision of a symptomatic craniopharyngioma during pregnancy: case report.

A 27-year-old woman in the second trimester of pregnancy presented with bitemporal hemianopsia. Total resection of a craniopharyngioma restored normal vision, and she delivered a normal infant at term. Permanent hormonal replacement therapy was not needed.

Partial care in mental health organizations: United States and each state, 1988.

Partial care is a relatively new and rapidly-growing form of mental health care consisting of a planned program of mental health treatment services generally provided in visits of 3 or more hours to groups of patients/clients. In 1970, only one-fourth of U.S.

Patient care episodes in mental health organizations, United States: selected years from 1955 to 1988.

The 4,930 mental health organizations providing mental health services in the United States during 1988 (excluding the Territories) generated just over 8.3 million patient care episodes (table 1). However, in order to compare 1988 data with those for other years dating back to 1955, outpatient and partial care programs administered by the Department of Veterans Affairs (formerly the Veterans Administration) (VA) need to be omitted (table 2).

Availability and distribution of psychiatric beds, United States and each state, 1988.

The total number of non-Federal and Department of Veterans Affairs (VA) inpatient and residential treatment psychiatric beds in mental health organizations in the United States increased by almost 2 percent between 1986 and 1988, from 267,613 to 271,923. Excluding VA psychiatric beds in both years, the number of beds increased from 240, 739 in 1986 to 246,181 in 1988 (2.3 percent).