A child has a 1 in 2000 chance of developing leukemia by the age of 15. The most common types of childhood leukemia typically exhibit gross chromosomal abnormalities. While the consequences of some of these abnormalities are understood, much less is known about how these genomic derangements occur in the first place, or how environmental factors affect the frequency of their occurrence. Tumor-associated chromosomal aberrations result from destabilizing DNA transactions, including V(D)J recombination, a form of programmed DNA rearrangement that normally serves to assemble antigen receptor genes. In preliminary work we have defined molecular mechanisms that constrain V(D)J recombination in time and in space, and have proceeded to demonstrate that mistimed recombination is associated with genomic instability and lymphomagenesis. Building on these accomplishments, the work proposed under this proposal aims to develop a mechanistic understanding of genomic instability in leukemic progenitors, to build new tools to uncover functional interactions between gross chromosomal abnormalities and cooperating mutations, and to define epigenetic mechanisms that may protect the genome by limiting the destabilizing effects of V(D)J recombinase activity. Under the first aim we will elucidate mechanisms by which posttranslational regulation of recombinase activity enforces genomic integrity in developing lymphoid cells.
This aim i s of particular importance because it is expected to shed light on mechanisms that initiate chromosomal rearrangements in leukemias and other malignancies. Under the second aim we will exploit the genomic plasticity associated with unscheduled V(D)J recombination to identify lymphomagenic interactions between chromosomal translocations and smaller genetic lesions.
The third aim will define a specific mechanism by which the transcriptional activation of chromatin constrains V(D)J recombination to particular sites during normal and abnormal development. Thus the overarching themes of this proposal are to elucidate mechanisms that control genomic plasticity in developing lymphoid cells and to determine the relationships between these controls and intrinsic defenses against lymphoid cancer.
Cancers of lymphoid cells are among the most common life-threatening diseases of childhood. Abnormal rearrangements of chromosomal DNA contribute to the development of most of these cancers. Work under this project will help provide a framework for understanding how these abnormal rearrangements occur and may ultimately lead to novel methods for prediction, diagnosis and treatment.
|Lu, Chao; Ward, Alyssa; Bettridge, John et al. (2015) An autoregulatory mechanism imposes allosteric control on the V(D)J recombinase by histone H3 methylation. Cell Rep 10:29-38|
|Halper-Stromberg, Eitan; Steranka, Jared; Giraldo-Castillo, Nicolas et al. (2013) Fine mapping of V(D)J recombinase mediated rearrangements in human lymphoid malignancies. BMC Genomics 14:565|
|Rybanska-Spaeder, Ivana; Reynolds, Taylor L; Chou, Jeremy et al. (2013) 53BP1 is limiting for NHEJ repair in ATM-deficient model systems that are subjected to oncogenic stress or radiation. Mol Cancer Res 11:1223-34|
|Thapa, Puspa; Das, Joy; McWilliams, Douglas et al. (2013) The transcriptional repressor NKAP is required for the development of iNKT cells. Nat Commun 4:1582|