ABSTRACT
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic neoplasm resulting from the malignant transformation of T-cell progenitors, and comprises ~15% and 25% of pediatric and adult ALL cases, respectively. It is well-established that activating NOTCH1 mutations are the major genetic lesions driving T-ALL in most patients, but efforts to develop targeted therapies against this pathway have produced limited success in decreasing leukemic burden and come with significant clinical side effects. A finer detailed understanding of the genetic and molecular mechanisms underlying T-ALL is required identify patients at increased risk for treatment failure and the development of precision medicine strategies. Generation of genetic models that more accurately reflect the normal developmental history of T-ALL are necessary to identify new avenues for treatment. The DNA methyltransferase enzyme DNMT3A is also recurrently mutated in T-ALL patients, and we show here that inactivation of Dnmt3a combined with Notch1 gain-of-function leads to an aggressive T-ALL in mouse models. Moreover, conditional inactivation of Dnmt3a in mouse hematopoietic cells leads to an accumulation of immature progenitors in the thymus, which are less apoptotic. These data demonstrate that Dnmt3a is required for normal T-cell development, and acts as a T-ALL tumor suppressor.
Subject(s)
DNA (Cytosine-5-)-Methyltransferases/physiology , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology , T-Lymphocytes/cytology , Animals , Apoptosis , Cell Line , DNA (Cytosine-5-)-Methyltransferases/genetics , DNA Methylation , DNA Methyltransferase 3A , Humans , Mice , Mice, Inbred C57BL , Mice, KnockoutABSTRACT
Infant leukemia (IL) is a rare sporadic cancer with a grim prognosis. Although most cases are accompanied by MLL rearrangements and harbor very few somatic mutations, less is known about the genetics of the cases without MLL translocations. We performed the largest exome-sequencing study to date on matched non-cancer DNA from pairs of mothers and IL patients to characterize congenital variation that may contribute to early leukemogenesis. Using the COSMIC database to define acute leukemia-associated candidate genes, we find a significant enrichment of rare, potentially functional congenital variation in IL patients compared with randomly selected genes within the same patients and unaffected pediatric controls. IL acute myeloid leukemia (AML) patients had more overall variation than IL acute lymphocytic leukemia (ALL) patients, but less of that variation was inherited from mothers. Of our candidate genes, we found that MLL3 was a compound heterozygote in every infant who developed AML and 50% of infants who developed ALL. These data suggest a model by which known genetic mechanisms for leukemogenesis could be disrupted without an abundance of somatic mutation or chromosomal rearrangements. This model would be consistent with existing models for the establishment of leukemia clones in utero and the high rate of IL concordance in monozygotic twins.
Subject(s)
Biomarkers, Tumor/genetics , Gene Rearrangement , Leukemia, Myeloid, Acute/genetics , Mutation/genetics , Myeloid-Lymphoid Leukemia Protein/genetics , Polymorphism, Single Nucleotide/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Adult , Case-Control Studies , Child , Female , Histone-Lysine N-Methyltransferase , Humans , Infant , Leukemia, Myeloid, Acute/congenital , Male , Precursor Cell Lymphoblastic Leukemia-Lymphoma/congenital , Prognosis , Survival Rate , Young AdultABSTRACT
We have examined our prospectively collected experience with femoral artery closure devices. Vasoseal (n = 937), Angioseal (N-742), and Techstar (n = 1001) were utilized consecutively in our laboratory for diagnostic and interventional femoral artery closures. Complications were compared to a similar number of closures with manual compression (MC; n = 1019) before closure devices were utilized. The incidence of surgical repair, acute femoral closure, transfusion due to groin complications, readmission for groin complications, infection, and total complications were examined. We found that the Vasoseal and Angioseal devices were associated with higher rates of total complications than manual compression. The Techstar and manual compression had similar total complication rates. Acute femoral artery occlusion was a potentially serious complication with the Angioseal device. Groin infection occurred with each of the closure devices but not with manual compression.
Subject(s)
Cardiac Catheterization/adverse effects , Cardiac Catheterization/instrumentation , Catheters, Indwelling/adverse effects , Femoral Artery/physiopathology , Adult , Aged , Analysis of Variance , Equipment Design , Equipment Safety , Female , Humans , Male , Middle Aged , Prospective Studies , Reference ValuesABSTRACT
Dermatology emerged as a distinct medical specialty in the mid-1800s. The background that led to this development, and the contributions made to the specialty by pioneering physicians in England, France, the German-speaking countries, and the United States are discussed.