Defining the Mechanism of Genome Rearrangements in Ph-Like ALL to Determine Predictive Markers in High-Risk Hispanic Populations

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PROJECT SUMMARY/ABSTRACT Philadelphia chromosome-like B cell acute lymphoblastic leukemia (Ph-like ALL) is an ALL subtype that disproportionately affects the Hispanic community and is characterized as having a poor response to therapy, a high risk of relapse, and a peak onset in adolescents and young adults. While lacking a BCR-ABL fusion, nearly 65% of Ph-like ALL cases carry a rearrangement in the cytokine receptor-like factor 2 (CRLF2) gene, the most common being a chromosomal translocation with the immunoglobulin heavy chain locus (CRLF2-IgH) resulting in overexpression of CRLF2 and low survival. One comparative study found that Ph-like ALL occurred in 68% of Hispanics versus 23% of Whites and of those, 78% of Hispanics had disease associated with CRLF2 rearrangements compared to 22% of Whites, indicating a clear cancer disparity. The long-term goal is to develop predictive diagnostics based upon a patient’s genetic background to address cancer disparities. The overall objectives for this proposal are to leverage genetic and molecular expertise on the etiology of B cell malignancies to determine the mechanism underlying CRLF2-IgH formation and determine how changing levels of B cell-specific factors and epigenetic imprinting predispose Hispanics to this translocation and thus Ph-like ALL. The central hypothesis is that DNA double-strand breaks (DSBs) leading to CRLF2-IgH translocations result from a mechanism involving activation-induced cytidine deaminase (AID) and DNA methylation and that differential regulation of these processes in Hispanics is driving the cancer disparity. The rationale for this project stems from results showing that CRLF2 DSBs resulting in CRLF2-IgH translocations are highly enriched in a 311 bp cluster region. DSBs within this cluster occur at motifs recognized by AID and these motifs contain CpG sequences that are also sites of DNA methylation. Evidence shows that meCT deamination is more detrimental that CU deamination and more likely to result in DSBs. Determining if aberrant AID expression and changing DNA methylation patterns account for increased CRLF2-IgH formation in Hispanics is critical in addressing the Ph-like ALL disparity and will be tested through three specific aims: 1) Define the molecular mechanism of CRLF2-IgH formation; 2) Determine genetic and epigenetic factors underlying Ph-like ALL disparities in Hispanics; and 3) Develop a molecular assay to detect CRLF2-IgH translocations and compare treatment response in Hispanics and non-Hispanics. The innovative aspects of this work are identification of a 311 bp DSB cluster associated with CRLF2 instability, application of new molecular and genomic techniques in human cells to address the etiology of Ph-like ALL, and the use of patient material from the UCI comprehensive cancer center that serves a large Hispanic population. This work is significant as it will address a major cancer health disparity in the Hispanic community and develops a novel diagnostic for early detection of new or relapsed disease while at the same time unravelling a molecular mechanism that is not only relevant to Ph-like ALL, but also to several additional B cell malignancies.