September 8, 2016
Keeping up with HIV mutations: Building a nimble vaccine test system
An AIDS vaccine able to fight any HIV strain has thus far eluded science. HIV frequently mutates its coat protein, dodging vaccine makers’ efforts to elicit sufficiently broadly neutralizing antibodies.
Yet sometimes HIV-infected people can produce such antibodies on their own. This usually requires years of exposure to the virus, allowing the immune system to modify its antibodies over time to keep up with HIV mutations. But the goal is generally achieved too late in the game to prevent them from being infected.
“Only a small fraction of patients are able to develop broadly neutralizing antibodies, and by the time they do, the virus has already integrated into the genomes of their T-cells,” says Ming Tian, PhD, of Boston Children’s Hospital’s Program in Cellular and Molecular Medicine (PCMM).
Tian is part of a group led by PCCM director Frederick Alt, PhD, that developed a technology to greatly speed up HIV development. Described today in Cell, the group’s method generates mouse models with built-in human immune systems. The model recapitulates what the human immune system does, only much more rapidly, enabling researchers to continuously test and tweak potential HIV vaccines.
| August, 26, 2016
Pei-Chi Wei was awarded Charles A. King Trust Postdoctoral Fellowships
Dr. Wei (right) a postdoctoral fellow in the Alt lab has previously identified classes of recurrent DNA double strand breaks (RDC) that occurred frequently in the body of long genes in murine neural stem and progenitor cells (NSPCs). These genes have been implicated in neuropsychiatric diseases and many are rearranged in cancers, including brain cancers. Dr. Wei aims to elucidate the roles of RDCs in NSPCs in neuronal cell diversification and brain diseases development.Dr. Wei a postdoctoral fellow in the Alt lab has previously identified classes of recurrent DNA double strand breaks (RDC).
Dr. Cheng-Sheng Lee was awarded the Cancer Research Institute Irvington Postdoctoral Fellowship
During this fellowship Dr. Lee will investigate how recombination activating gene endonuclease (RAG) mediates recombination between bona fide RAG recognition sequences (RRSs). Specifically, Dr. Lee will examine the mechanism of RAG tracking, a model originally proposed to explain the RAG off-target joining happened exclusively between convergent RSSs in topologically associated domains. He will also investigate driving forces that propel RAG tracking through a chromosomal loop. The proposed work will help provide fundamental understanding of normal antibody repertoire development and mechanisms of chromosomal translocations in lymphoid cancers.
| May 26, 2016
Congratulations to Rohit Panchakshari
Congratulations to Rohit Panchakshari, a graduate student in the Alt lab for a successful defense of his Ph.D. thesis entitled "Investigating Mechanisms of DNA Double Strand Break joining of Switch regions during IgH Class Switch Recombination".
| March 2, 2016
Dr. Huan Chen Received Career Development Fellowship from the Leukemia & Lymphoma Society
During this fellowship Dr. Chen, a postdoctoral fellow in the laboratory of Dr. Fred Alt, will elucidate the mechanistic components and physiologic function of alternative end joining (A-EJ), a DNA double-strand break (DSB) repair pathway that likely contributes to lymphoid and other tumors. She will study A-EJ in the context of IgH class switch recombination (CSR) using a newly developed high throughput genome wide translocation sequencing (HTGTS)-based assay. Fully characterizing A-EJ will help to understand the onset and progression of some blood cancers and reveal novel targets for cancer treatment.
| February 25, 2016
Fred Alt received Willian Silen Lifetime Achievement in Mentoring Award from Harvard Medical School
Dr. Frederick W. Alt received William Silen Lifetime Achievement in Mentoring Award from Harvard Medical School in recognition of Dr. Alt's impact on professional development and career advancement in research.
February 11, 2016
Adopted from Boston Children's Hospital News Release
DNA breaks in nerve cells' ancestors cluster in specific genes
Study reveals new avenue for thinking about brain development, brain tumors and neurodevelopmental/psychiatric diseases
By Tom Ulrich
The genome of developing brain cells harbors 27 clusters, or hotspots, where its DNA is much more likely to break in some places than others, according to research from Harvard Medical School and Boston Children’s Hospital.
Those hotspots appear in genes associated with brain tumors and a number of neurodevelopmental and neuropsychiatric conditions.
The findings, reported Feb. 11 in Cell, raise new questions about the origins of these conditions as well as how the brain generates a diversity of circuitry during development.
| January 5, 2016
Dr. Zhaoqing Ba was awarded the Cancer Research Institute Irvington Postdoctoral Fellowship
Dr. Ba, a postdoctoral fellow in the Alt lab, will investigate the mechanisms that mediate the intra-locus and inter-locus regulation of V(D)J recombination at Ig kappa and Ig lambda loci during B cell development, and identify RAG off-target activities genome-wide. This work will provide new insights into mechanisms of chromosomal translocations associated with leukemias and lymphomas and ultimately could provide insights into minimizing or preventing such aberrant events.
|November 12, 2015
Using passenger alleles to elucidate the targeting of AID in immunity
by Paul Guttry
Researchers in the laboratory of Frederick Alt at the Howard Hughes Medical Institute and Program in Cellular and Molecular Medicine (PCMM) at Boston Children's Hospital, led by Leng-Siew Yeap and Joyce K. Hwang, have fundamentally changed our understanding of how the crucial mutagenic activity of activation-induced cytidine deaminase (AID) is targeted during antibody maturation.
In an article published online in Cell on November 19, 2015, they demonstrate that the DNA sequence encoding the antigen-binding variable (V) region of B-cell antibodies lies in a genomic location privileged for mutational diversification by AID. Their study further reveals that no specialized mechanism beyond sufficient exposure to AID is required to generate antibodies whose neutralizing function depends on high levels of variable-region mutations and deletions.
| October 22, 2015
Genomic loops keep genes and enzymes on track and out of trouble
The looping organization of DNA may itself be a basic form of gene control
BOSTON, Oct. 22, 2015 /PRNewswire-USNewswire/ -- A study of where and how an enzyme cuts DNA may have inadvertently revealed a basic principle of gene regulation, say researchers in Boston Children's Hospital's Program in Cellular and Molecular Medicine (PCMM). The study, reported in the journal Cell, suggests that the cell can lock or "sandbox" genes and enzymes that act on them within loops of DNA and protein, confining their activity to minimize the risk of genetic disaster.
In our cells, DNA and its associated proteins—a combination called chromatin—are folded and wrapped in complex ways to form chromosomes. Researchers have long noted within a chromosome, the chromatin is organized into a series of loops. These loops can range in size from a few thousand to nearly 2.5 million base pairs, large enough to contain one or more complete genes.
The study team—led by co-first authors Jiazhi Hu, PhD, and Yu Zhang, PhD, and senior author Frederick Alt, PhD—believes these loops may form the backbone of a fundamental organizing principle for genomic processes.
| May 22, 2015
Dr. Frederick W. Alt received the 2015 Katherine Berkan Judd Award from the Memorial Sloan Kettering Cancer Center.
This award is given annually for Distinguished Achievement in Biomedical Research. The Judd Award was established in 1936 by Mrs. Judd. She had the foresight and vision to realize that, in the future, scientists would make great strides towards the control and understanding of cancer through basic discovery. Toward that end, she provided that a portion of her estate be designated as the Katherine Berkan Judd Cancer Fund. Dr. Alt was selected to receive the Judd award this year for his contributions to understanding DNA repair pathways the mediate recombination in the immune system, and the relevance of these pathways to chromosomal translocation and oncogenesis.
| April 29, 2015
Frederick Alt honored with 2015 Szent-Györgyi Prize for Progress in Cancer Research
Frederick Alt, PhD, director of the Program in Cellular and Molecular Medicine at Boston Children's Hospital, has been honored with the 2015 Szent-Györgyi Prize for Progress in Cancer Research. Awarded by the National Foundation for Cancer Research (NFCR), the prize recognizes Alt's groundbreaking work on the genetic nature of cancer, research that laid the foundation for our modern understanding of cancer and for the current revolution in personalized, targeted cancer treatment.
The Keynote speech at the award ceremony was delivered by Edward Markey, United States Senator for Massachusetts
April 13, 2015
Congratulations to Fred Alt, Recipient of the 44th Rosenstiel Award for Distinguished Work in Biomedical Science
The 44th Rosenstiel Award for Distinguished Work in Biomedical Science has been awarded to Dr. Frederick W. Alt, the Director of the Program in Cellular and Molecular Medicine at Boston Children’s Hospital. He is also Charles A. Janeway Professor of Pediatrics and Professor of Genetics, Harvard Medical School and Investigator of the Howard Hughes Medical Institute. Dr. Alt is honored for his pioneering work in elucidating the mechanisms of genome rearrangements in immune and cancer cells.