AMP-activated protein kinase links acetyl-CoA homeostasis to BRD4 recruitment in acute myeloid leukemia.

Altered metabolism fuels 2 hallmark properties of cancer cells: unlimited proliferation and differentiation blockade. Adenosine monophosphate-activated protein kinase (AMPK) is a master regulator of bioenergetics crucial for glucose metabolism in acute myeloid leukemia (AML), and its inhibition delays leukemogenesis, but whether the metabolic function of AMPK alters the AML epigenome remains unknown. Here, we demonstrate that AMPK maintains the epigenome of MLL-rearranged AML by linking acetyl-coenzyme A (CoA) homeostasis to Bromodomain and Extra-Terminal domain (BET) protein recruitment to chromatin. AMPK deletion reduced acetyl-CoA and histone acetylation, displacing BET proteins from chromatin in leukemia-initiating cells. In both mouse and patient-derived xenograft AML models, treating with AMPK and BET inhibitors synergistically suppressed AML. Our results provide a therapeutic rationale to target AMPK and BET for AML therapy.

PRDM16s transforms megakaryocyte-erythroid progenitors into myeloid leukemia-initiating cells.

Oncogenic mutations confer on cells the ability to propagate indefinitely, but whether oncogenes alter the cell fate of these cells is unknown. Here, we show that the transcriptional regulator PRDM16s causes oncogenic fate conversion by transforming cells fated to form platelets and erythrocytes into myeloid leukemia stem cells (LSCs). Prdm16s expression in megakaryocyte-erythroid progenitors (MEPs), which normally lack the potential to generate granulomonocytic cells, caused AML by converting MEPs into LSCs. Prdm16s blocked megakaryocytic/erythroid potential by interacting with super enhancers and activating myeloid master regulators, including PU.1. A CRISPR dropout screen confirmed that PU.1 is required for Prdm16s-induced leukemia. Ablating PU.1 attenuated leukemogenesis and reinstated the megakaryocytic/erythroid potential of leukemic MEPs in mouse models and human AML with PRDM16 rearrangement. Thus, oncogenic PRDM16 s expression gives MEPs an LSC fate by activating myeloid gene regulatory networks.

A stone miner with both silicosis and constrictive pericarditis: case report and review of the literature.

BACKGROUND: The working environment of stone miners has been believed to cause their susceptibility to respiratory diseases. Silicosis is an occupational disease caused by exposure to crystalline silica dust which is marked by inflammation and scarring in the lung. The immune system boosted after the silica invasion led to self-damage and lay the foundation of silicosis pathogenesis. Silicosis coexisting with other diseases in one patient has been reported, however, was not reported to coexist with constrictive pericarditis. We, for the first time, reported a patient with silicosis and constrictive pericarditis and thought the immune response was probably the link between the two. CASE PRESENTATION: A 59-year-old Chinese stone miner complained of chest distress was found to have lung nodules which were found to be silica deposits by biopsy. This patient was also found to have constrictive pericarditis at the same time. Later surgical decortication cured his symptoms. CONCLUSION: We provided the first case having constrictive pericarditis concomitant with silicosis. A probable link between the two diseases was the immune response boosted by the silica deposits.

Discovery of novel candidate oncogenes in pancreatic carcinoma using high-throughput microarrays.

BACKGROUND/AIMS: Pancreatic cancer is one of the most aggressive tumors in mankind. Its aggressiveness is only due to the biological progressive characteristics but also the difficulty for clinical early detection which urges us to find diagnostic tools for early diagnosis. Biomarkers are a developing tool used to measure molecules such as proteins, DNA, or RNAs in blood samples or suspected tumor tissues. The molecular dysregulation is believed to play major roles in tumorigenesis or a result after the tumor formation and can be used as a biomarker for tumor detection. METHODOLOGY: In this paper, we studied the gene expression profiles using tissues from pancreatic cancer patients. RESULTS: We observed dysregulation of gene expression profiles using high-throughput sequencing technique and verified three-gene upregulation, REG4, CDH3 and S100P both in pancreatic cell lines and carcinoma tissues by RT-PCR and Northern Blot. A detailed description of the genes involved is listed within this article. CONCLUSIONS: We believe that by unraveling the gene dysregulation profiles in pancreatic tumor tissues can we achieve an early and precise diagnosis of pancreatic cancer. Moreover, these newly found genes, due to their functions involved in cell migration and mitosis, may play major roles in tumorigensis.

[K83 site affects PICK1 PDZ binding ability].

OBJECTIVE: To investigate the role of 83 site in interaction of GluR2 C-terminal and PICK1 PDZ domain. METHODS: Docking structure of PICK1 PDZ domain with GluR2 C terminal PDZ binding motif was built with computer software. After K83 site was substituted by other amino acid, the structure and binding energy were recalculated; meanwhile, site specific mutants were constructed using wild type full length cDNA as template. Mutants were co-transfected with GluR2 into HEK293T cells. After staining, the distribution of PICK1 and GluR2 were observed under confocal microscope. RESULTS: Wild type PICK1 and GluR2 formed many co-clusters in HEK293T cells as reported by other research groups; but different K83 mutant had different distribution in HEK293T cells. CONCLUSION: The K83 site in PDZ domain of PICK1 is important for the interaction between PICK1 and GluR2. Altering lysine will probably change the hydrophobic interactions, the hydrogen bonds or the electrostatic interactions formed between PICK1 PDZ domain and GluR2 C terminal; accordingly, that will change the binding capacity between PICK1 and GluR2 in varying degrees.

An oncogenic enhancer encodes selective selenium dependency in AML.

Deregulation of transcription is a hallmark of acute myeloid leukemia (AML) that drives oncogenic expression programs and presents opportunities for therapeutic targeting. By integrating comprehensive pan-cancer enhancer landscapes with genetic dependency mapping, we find that AML-enriched enhancers encode for more selective tumor dependencies. We hypothesized that this approach could identify actionable dependencies downstream of oncogenic driver events and discovered a MYB-regulated AML-enriched enhancer regulating SEPHS2, a key component of the selenoprotein production pathway. Using a combination of patient samples and mouse models, we show that this enhancer upregulates SEPHS2, promoting selenoprotein production and antioxidant function required for AML survival. SEPHS2 and other selenoprotein pathway genes are required for AML growth in vitro. SEPHS2 knockout and selenium dietary restriction significantly delay leukemogenesis in vivo with little effect on normal hematopoiesis. These data validate the utility of enhancer mapping in target identification and suggest that selenoprotein production is an actionable target in AML.

Nuclear NAD+ homeostasis governed by NMNAT1 prevents apoptosis of acute myeloid leukemia stem cells.

Metabolic dysregulation underlies malignant phenotypes attributed to cancer stem cells, such as unlimited proliferation and differentiation blockade. Here, we demonstrate that NAD+ metabolism enables acute myeloid leukemia (AML) to evade apoptosis, another hallmark of cancer stem cells. We integrated whole-genome CRISPR screening and pan-cancer genetic dependency mapping to identify NAMPT and NMNAT1 as AML dependencies governing NAD+ biosynthesis. While both NAMPT and NMNAT1 were required for AML, the presence of NAD+ precursors bypassed the dependence of AML on NAMPT but not NMNAT1, pointing to NMNAT1 as a gatekeeper of NAD+ biosynthesis. Deletion of NMNAT1 reduced nuclear NAD+, activated p53, and increased venetoclax sensitivity. Conversely, increased NAD+ biosynthesis promoted venetoclax resistance. Unlike leukemia stem cells (LSCs) in both murine and human AML xenograft models, NMNAT1 was dispensable for hematopoietic stem cells and hematopoiesis. Our findings identify NMNAT1 as a previously unidentified therapeutic target that maintains NAD+ for AML progression and chemoresistance.

Clonal expansion and myeloid leukemia progression modeled by multiplex gene editing of murine hematopoietic progenitor cells.

Recent advances in next-generation sequencing have identified novel mutations and revealed complex genetic architectures in human hematological malignancies. Moving forward, new methods to quickly generate animal models that recapitulate the complex genetics of human hematological disorders are needed to transform the genetic information to new therapies. Here, we used a ribonucleoprotein-based CRISPR/Cas9 system to model human clonal hematopoiesis of indeterminate potential and acute myeloid leukemia (AML). We edited multiple genes recurrently mutated in hematological disorders, including those encoding epigenetic regulators, transcriptional regulators, and signaling components in murine hematopoietic stem/progenitor cells. Tracking the clonal dynamics by sequencing the indels induced by CRISPR/Cas9 revealed clonal expansion in some recipient mice that progressed to AML initiated by leukemia-initiating cells. Our results establish that the CRISPR/Cas9-mediated multiplex mutagenesis can be used to engineer a variety of murine models of hematological malignancies with complex genetic architectures seen in human disease.

Cell intrinsic and extrinsic regulation of leukemia cell metabolism.

Metabolic homeostasis is a fundamental property of cells that becomes dysregulated in cancer to meet the altered, often heightened, demand for metabolism for increased growth and proliferation. Oncogenic mutations can directly change cellular metabolism in a cell-intrinsic manner, priming cells for malignancy. Additionally, cell-extrinsic cues from the microenvironment, such as hypoxia, nutrient availability, oxidative stress, and crosstalk from surrounding cells can also affect cancer cell metabolism, and produce metabolic heterogeneity within the tumor. Here, we highlight recent findings revealing the complexity and adaptability of leukemia cells to coordinate metabolism.

The R900S mutation in CACNA1S associated with hypokalemic periodic paralysis.

Primary hypokalemic periodic paralysis is an autosomal dominant skeletal muscle channelopathy. In the present study, we investigated the genotype and phenotype of a Chinese hypokalemic periodic paralysis family. We used whole-exome next-generation sequencing to identify a mutation in the calcium channel, voltage-dependent, L type, alpha subunit gene (CACNA1S), R900S, which is a rare mutation associated with hypokalemic periodic paralysis. We first present a clinical description of hypokalemic periodic paralysis patients harboring CACNA1SR900S mutations: they were non-responsive to acetazolamide, but combined treatment with triamterene and potassium supplements decreased the frequency of muscle weakness attacks. All male carriers of the R900S mutation experienced such attacks, but all three female carriers were asymptomatic. This study provides further evidence for the phenotypic variation and pharmacogenomics of hypokalemic periodic paralysis.

Hyperthyroidism with concurrent FMS-like tyrosine kinase 3-internal tandem duplication-positive acute promyelocytic leukemia: A case report and review of the literature.

Neutropenia is a common side-effect in hyperthyroid patients with long-term use of antithyroid drugs. This may be caused by drug-induced immune dysfunction or increased thyroxine hematologic toxicity, which usually returns to normal after medication is discontinued or the hyperthyroidism becomes well controlled. However, hyperthyroidism with pancytopenia is extremely rare. The current case report presents a hyperthyroid patient complicated with pancytopenia who had taken antithyroid drugs for 14 years. Bone marrow analysis revealed primary leuokocytes, indicating M3 acute leukemia. Genetic analysis revealed promyelocytic leukemia-retinoic acid receptor α fusion and FMS-like tyrosine kinase 3-internal tandem duplication. The genetic abnormality was also associated with thyroid hormonal functions. After a standard anti-M3 regimen was administed, the patient achieved complete remission and maintained stable thyroid functions. To the best of our knowledge, this is the first reported case of a patient with hyperthyroidism acquiring M3 leukemia harboring the FMS-like tyrosine kinase 3-internal tandem duplication.

An aggressive form of non-Hodgkin's lymphoma with pleural and abdominal chylous effusions: A case report and review of the literature.

Serous effusions, including pleural, abdominal and pericardial effusions, are complications of lymphoma. Among these types, pleural effusions are the most common to be observed. However, the involvement of the abdominal or pericardial cavity is rare. An impairment of the lymphatic drainage and direct infiltration have been identified to play significant roles in effusion formation. Multiple techniques, including cytological exams, immunochemistry and cytogenetics, have been applied in the clinic to access the qualities of the effusions and to attain a fast and precise diagnosis. Serous effusions are associated with a poor outcome for patients with lymphoma. The present study describes the case of a 28-year-old male patient with aggressive non-Hodgkin's lymphoma (NHL) involving pleural and abdominal chylous effusions.

RNA secondary structure in mutually exclusive splicing.

Mutually exclusive splicing is a regulated means to generate protein diversity, but the underlying mechanisms are poorly understood. Here comparative genome analysis revealed the built-in intronic elements for controlling mutually exclusive splicing of the 14-3-3ξ pre-mRNA. These elements are clade specific but are evolutionarily conserved at the secondary structure level. Combined evidence revealed the triple functions of these inter-intronic RNA pairings in synergistically ensuring the selection of only one of multiple exons, through activation of the proximal variable exon outside the loop by the approximation of cis elements, and simultaneous repression of the exon within the loop, in combination with the physical competition of RNA pairing. Additionally, under this model, we also deciphered a similar structural code in exon clusters 4 and 9 of Dscam (38,016 isoforms) and Mhc (480 isoforms). Our findings suggest a broadly applicable mechanism to ensure mutually exclusive splicing.