How do blood cancers develop?

Our immune system always do strange things out of control. For example, when it makes small mistakes, the body amplifies its response to a large extent. It will edit errors in the DNA of developing T and B cells can cause blood cancers.

Recently, researchers from the Perelman School of Medicine, University of Pennsylvania have shown that when the enzyme key to cutting and pasting segments of DNA hits so-called "off-target" spots on a chromosome, the development of immune cells can lead to cancer in animal models. Learning about the nature of these editing errors is quite helpful in designing therapeutic enzymes based on these molecular scissors.

V(D)J recombinase, the editing enzyme that generates specific receptors on the surface of immune cells that match foreign invaders, collectively called antigens, can miss its target from time to time. V(D)J recombinase works only in the early stage of immune cell maturation. In this stage, the diverse array of antibodies and cell-surface receptors found on immune B cells and T cells are respectively made to counteract all the foreign invaders the human body encounters.

Breaks in DNA strands associated with V(D)J cutting are normally repaired with high fidelity by finely tuned molecular machinery. Previous studies from the Roth lab showed that V(D)J recombinase (consisting of the RAG1 and RAG2 proteins) normally sends a break in DNA down the correct repair path by preventing access to other, inappropriate repair mechanisms. This shepherding process can be disabled if the "C" terminus of the RAG2 protein subunit is removed. This causes genomic instability in developing immune cells and, in the absence of a working tumor suppressor protein such as p53, an aggressive form of lymphoma develops in mice.

According to David Roth, the lab of senior author, MD, PhD, chair of the Department of Pathology and Laboratory Medicine, genome wide analysis of lymphomas of the thymus in these mice with the truncated Rag2 protein revealed a surprise: numerous off-target DNA rearrangements, causing deletions. And these rearrangements affected several known and suspected oncogenes and tumor suppressor genes, such as Notch1, Pten, Ikzf1, Jak1, Phlda1, Trat1, and Agpat9.
We can learn more from the genomewide analysis of chromatin marks that normal interactions between the C-terminus of the Rag2 protein subunit and a specific chromatin modification helps maintain the fidelity of DNA target recognition by the enzyme.

It is noteworthy that the cancer-causing effects of off-target deletions mistakenly created by the V(D)J enzyme need to be considered in designing site-specific enzymes for genome modification such as zinc-finger nucleases, TALENS, or CRISPRs.

The Penn team's findings appear online this week in Cell Reports ahead of the print issue. All these foundings contribute much to treatment of blood cancers.

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