An Atypical Presentation of Hodgkin Lymphoma Invading the Myocardium.

Pericardial involvement by Hodgkin lymphoma has been found in up to 20% of children at presentation, but disease of the myocardium itself is rare. We describe an 18-year-old male with HL who presented with a large mediastinal mass, pericardial effusion, and tumor invasion of both atrial walls with intra-atrial extension. A PubMed search of publications between 1989 and 2022 was conducted and additional older references were identified among these publications.

Emergence of a Ph-negative Clone in a Child With Ph+ ALL.

The addition of tyrosine kinase inhibitors to conventional chemotherapy has improved outcomes for pediatric patients with Philadelphia chromosome-positive (Ph) acute lymphoblastic leukemia (ALL). However, the rate of relapse is still higher compared with many other types of pediatric ALL, with many possible mechanisms for resistance. We describe an 8-year-old boy with Ph ALL relapsing with ALL without the Ph following treatment with dasatinib as a part of Children's Oncology Group trial AALL1122.

Degree of recruitment of DOT1L to MLL-AF9 defines level of H3K79 Di- and tri-methylation on target genes and transformation potential.

The MLL gene is a common target of chromosomal translocations found in human leukemia. MLL-fusion leukemia has a consistently poor outcome. One of the most common translocation partners is AF9 (MLLT3).

An AF9/ENL-targted peptide with therapeutic potential in mixed lineage leukemias.

Misregulation of transcription elongation is proposed to underlie the pathobiology of MLL leukemia. AF4, AF9, and ENL, common MLL fusion partners, are found in complex with positive transcription elongation factor b (P-TEFb). AF9 and its homolog ENL directly interact with AF4 within these complexes.

Importance of a specific amino acid pairing for murine MLL leukemias driven by MLLT1/3 or AFF1/4.

Acute leukemias caused by translocations of the MLL gene at chromosome 11 band q23 (11q23) are characterized by a unique gene expression profile. More recently, data from several laboratories indicate that the most commonly encountered MLL fusion proteins, MLLT1, MLLT3, and AFF1 are found within a molecular complex that facilitates the elongation phase of mRNA transcription. Mutational analyses suggest that interaction between the MLLT1/3 proteins and AFF family proteins are required for experimental transformation of hematopoietic progenitor cells (HPCs).

CBX8, a component of the Polycomb PRC1 complex, modulates DOT1L-mediated gene expression through AF9/MLLT3.

AF9 is known to interact with multiple proteins including activators and repressors of transcription. Our data indicate that other AF9 binding proteins compete with the histone methyltransferase DOT1L for AF9 binding thus diminishing its ability to methylate lysine 79 of histone 3. Specifically, we show that AF9 is part of a protein multimer containing members of Polycomb group (PcG) PRC1 complex, CBX8, RING1B, and BMI1.

Histone H3 lysine 79 methyltransferase Dot1 is required for immortalization by MLL oncogenes.

Chimeric oncoproteins resulting from fusion of MLL to a wide variety of partnering proteins cause biologically distinctive and clinically aggressive acute leukemias. However, the mechanism of MLL-mediated leukemic transformation is not fully understood. Dot1, the only known histone H3 lysine 79 (H3K79) methyltransferase, has been shown to interact with multiple MLL fusion partners including AF9, ENL, AF10, and AF17.

Hsp90 directly modulates the spatial distribution of AF9/MLLT3 and affects target gene expression.

AF9/MLLT3 contributes to the regulation of the gene encoding the epithelial sodium channel alpha, ENaCalpha, in renal tubular cells. Specifically, increases in AF9 protein lead to a reduction in ENaCalpha expression and changes in AF9 activity appear to be an important component of aldosterone signaling in the kidney. Whereas AF9 is found in the nucleus where it interacts with the histone H3 lysine 79 methyltransferase, Dot1, AF9 is also present in the cytoplasm.

Molecular targeting of MLL-rearranged leukemia cell lines with the synthetic peptide PFWT synergistically enhances the cytotoxic effect of established chemotherapeutic agents.

MLL leukemias are characterized cytogenetically by reciprocal translocations of the MLL gene at 11q23 and clinically by unfavorable outcomes. Evidence indicating that MLL leukemias are resistant to apoptosis encourages the identification of agents that induce cell death by other mechanisms. The AF4-mimetic peptide PFWT induces necrosis in the t(4;11) leukemia cell line, MV4-11.

The AF4-mimetic peptide, PFWT, induces necrotic cell death in MV4-11 leukemia cells.

Despite ongoing success in the treatment of childhood acute lymphoblastic leukemia, patients harboring translocations involving the MLL gene at chromosome 11q23 remain resistant to treatment. To improve outcomes, novel therapeutics designed to target the unusual biology of these leukemias need to be developed. Previously, we identified an interaction between the two most common MLL fusion proteins, AF4 and AF9, and designed a synthetic peptide (PFWT) capable of disrupting this interaction.

Hurricane Katrina's impact on pediatric and adult patients with sickle cell disease.

Objective: Hurricane Katrina, making landfall in the U.S. in late August 2005, disrupted the medical infrastructure of New Orleans.

Dot1a-AF9 complex mediates histone H3 Lys-79 hypermethylation and repression of ENaCalpha in an aldosterone-sensitive manner.

Aldosterone is a major regulator of epithelial Na(+) absorption and acts in large part through induction of the epithelial Na(+) channel (ENaC) gene in the renal collecting duct. We previously identified Dot1a as an aldosterone early repressed gene and a repressor of ENaCalpha transcription through mediating histone H3 Lys-79 methylation associated with the ENaCalpha promoter. Here, we report a novel aldosterone-signaling network involving AF9, Dot1a, and ENaCalpha.

Potential of mesenchymal stem cells in gene therapy approaches for inherited and acquired diseases.

The intriguing biology of stem cells and their vast clinical potential is emerging rapidly for gene therapy. Bone marrow stem cells, including the pluripotent haematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs) and possibly the multipotent adherent progenitor cells (MAPCs), are being considered as potential targets for cell and gene therapy-based approaches against a variety of different diseases. The MSCs from bone marrow are a promising target population as they are capable of differentiating along multiple lineages and, at least in vitro, have significant expansion capability.

The mixed lineage leukemia fusion partner AF9 binds specific isoforms of the BCL-6 corepressor.

The mixed lineage leukemia (MLL) gene at chromosome band 11q23 is commonly involved in reciprocal translocations that are detected in acute leukemias. Evidence suggests that the resulting MLL fusion genes contribute to leukemogenesis. AF9 is a common MLL fusion partner in acute myeloid leukemia.