Rethinking paraneoplastic eosinophilia

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The Pediatric Cell Atlas:Defining the Growth Phase of Human Development at Single-Cell Resolution

Single-cell gene expression analyses of mammalian tissues have uncovered profound stage-specific molecular regulatory phenomena that have changed the understanding of unique cell types and signaling pathways critical for lineage determination, morphogenesis, and growth. We discuss here the case for a Pediatric Cell Atlas as part of the Human Cell Atlas consortium to provide single-cell profiles and spatial characterization of gene expression across human tissues and organs. Such data will complement adult and developmentally focused HCA projects to provide a rich cytogenomic framework for understanding not only pediatric health and disease but also environmental and genetic impacts across the human lifespan

DOT1L (DOT1 like histone H3K79 methyltransferase)

DOT1L is a histone lysine methyltransferase (KMT). It is the only known methyltransferase for lysine residue 79 on histone 3 (H3K79). The active site of DOT1L bears more homology to the active site in Protein Arginin Methyl Transferases (PRMTs) than the SET domain of other KMTs. DOT1L has important roles in normal development and cellular differentiation. DOT1L plays especially important roles in normal hematopoiesis and in leukemia. Initially characterized as a therapeutic target in MLL-rearranged acute leukemias, recent data suggest that DOT1L is also therapeutic target in other molecular subtypes of acute leukemia and in selected solid tumors. A phase 1 clinical trial of a small molecule inhibitor of Dot1L has been described, with encouraging responses being reported

The role of polycomb repressive complex 2 in early T-cell precursor acute lymphoblastic leukemia

Genetic lesions affecting polycomb repressive complex 2 (PRC2) have been found in more than 40% of pediatric cases of early T-cell precursor acute lymphoblastic leukemia. The functional role of these PRC2 alterations has been obscure. Our recent data suggest that compromise of PRC2 blocks differentiation and accentuates growth and survival signaling

<i>HOXA</i> Amplification Defines a Genetically Distinct Subset of Angiosarcomas

Angiosarcoma is a rare, devastating malignancy with few curative options for disseminated disease. We analyzed a recently published genomic data set of 48 angiosarcomas and noticed recurrent amplifications of HOXA-cluster genes in 33% of patients. HOXA genes are master regulators of embryonic vascular development and adult neovascularization, which provides a molecular rationale to suspect that amplified HOXA genes act as oncogenes in angiosarcoma. HOXA amplifications typically affected multiple pro-angiogenic HOXA genes and co-occurred with amplifications of CD36 and KDR, whereas the overall mutation rate in these tumors was relatively low. HOXA amplifications were found most commonly in angiosarcomas located in the breast and were rare in angiosarcomas arising in sun-exposed areas on the head, neck, face and scalp. Our data suggest that HOXA-amplified angiosarcoma is a distinct molecular subgroup. Efforts to develop therapies targeting oncogenic HOX gene expression in AML and other sarcomas may have relevance for HOXA-amplified angiosarcoma

The Functional Role of PRC2 in Early T-cell Precursor Acute Lymphoblastic Leukemia (ETP-ALL) – Mechanisms and Opportunities.

Early T-Cell Precursor Acute Lymphoblastic Leukemia (ETP-ALL) is a relatively newly identified subset of T-lineage ALL. There are conflicting results regarding prognosis, and the genetic basis of this condition is variable. Here we summarize the current status of the field and discuss the role of mutations in the Polycomb Repressive Complex 2 frequently identified in ETP-ALL patients