Single-cell RNA-sequencing reveals Transcriptional Changes and Clonal Architecture associated with Post-Transplant Relapse in Acute Myeloid Leukemia

"Acute myeloid leukemia (AML) is a malignancy characterized by overproduction of myeloid precursors at the expense of more differentiated, functional hematopoietic cells, resulting in anemia, thrombocytopenia, and neutropenia. Despite initial sensitivity to chemotherapy, a majority of patients with AML ultimately relapse. Among the challenges associated with relapse, post-allogeneic stem cell transplant relapse is particularly intractable because of our relative lack of understanding - and thus lack of effective treatment options - of the underlying mechanisms."--IntroductionZiheng Xu (1), Christopher A. Miller (2, 3), Sridhar N. Srivatsan (2), Catrina C. Fronick (3), Robert S. Fulton (3), Timothy J. Ley (2, 3, 4), and Allegra A. Petti (2, 3) ; 1. Washington University School of Medicine. 2. Division of Oncology, Washington University School of Medicine. 3. McDonnell Genome Institute, Washington University School of Medicine. 4. Department of Genetics, Washington University School of Medicine.Includes bibliographical reference

Sequence analysis in Bos taurus reveals pervasiveness of X–Y arms races in mammalian lineages

Studies of Y Chromosome evolution have focused primarily on gene decay, a consequence of suppression of crossing-over with the X Chromosome. Here, we provide evidence that suppression of X-Y crossing-over unleashed a second dynamic: selfish X-Y arms races that reshaped the sex chromosomes in mammals as different as cattle, mice, and men. Using super-resolution sequencing, we explore the Y Chromosome o

Genetic heterogeneity of induced pluripotent stem cells: results from 24 clones derived from a single C57BL/6 mouse.

This is the final version of the article. It first appeared from PLOS via http://dx.doi.org/10.1371/journal.pone.0120585Induced pluripotent stem cells (iPSCs) have tremendous potential as a tool for disease modeling, drug testing, and other applications. Since the generation of iPSCs "captures" the genetic history of the individual cell that was reprogrammed, iPSC clones (even those derived from the same individual) would be expected to demonstrate genetic heterogeneity. To assess the degree of genetic heterogeneity, and to determine whether some cells are more genetically "fit" for reprogramming, we performed exome sequencing on 24 mouse iPSC clones derived from skin fibroblasts obtained from two different sites of the same 8-week-old C57BL/6J male mouse. While no differences in the coding regions were detected in the two parental fibroblast pools, each clone had a unique genetic signature with a wide range of heterogeneity observed among the individual clones: a total of 383 iPSC variants were validated for the 24 clones (mean 16.0/clone, range 0-45). Since these variants were all present in the vast majority of the cells in each clone (variant allele frequencies of 40-60% for heterozygous variants), they most likely preexisted in the individual cells that were reprogrammed, rather than being acquired during reprogramming or cell passaging. We then tested whether this genetic heterogeneity had functional consequences for hematopoietic development by generating hematopoietic progenitors in vitro and enumerating colony forming units (CFUs). While there was a range of hematopoietic potentials among the 24 clones, only one clone failed to differentiate into hematopoietic cells; however, it was able to form a teratoma, proving its pluripotent nature. Further, no specific association was found between the mutational spectrum and the hematopoietic potential of each iPSC clone. These data clearly highlight the genetic heterogeneity present within individual fibroblasts that is captured by iPSC generation, and suggest that most of the changes are random, and functionally benign.This work was supported by grants from the NIH (CA101937 and CA162086, to TJL, and HL116605, to JMK), the Barnes Jewish Hospital Foundation (00335-0505-02, to TJL), and the Burroughs Wellcome Fund (to JMK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript