The T-cell Specific Element Activates The TAL1Oncogene Via Chromosomal Interaction In Human T-cell Acute Lymphoblastic Leukemia

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignantdisease of thymocytes that mainly affects children and has very poor prognosis withhigh rates of relapse. A prominent feature observed in60%of T-ALL patients is theectopic expression of a key hematopoietic transcription factor TAL1/SCL.TAL1/SCL is a critical transcription factor required for development of allhematopoietic lineages; yet, aberrant TAL1transcription which is frequentlyobserved in T-cell acute lymphoblastic leukemia (T-ALL), leads to leukemiamanifestation. It remains currently unknown how TAL1is activated in the majority ofT-ALL patients lacking the TAL1locus rearrangements.To understand the molecular mechanism underlying regulation of the TAL1oncogene in leukemic T-cells, we employed circularized chromosome conformationcapture (4C) methodology to identify new regulatory elements that activate TAL1specifically in T-ALL leukemia. Using the TAL1promoter1a as the bait, wediscovered that the TAL1promoter1a interacts with the TIL16element (TAL1interacting locus in chromosome16) that is located at~15Kb downstream of T-cellspecific CD2BP2gene in T-ALL cell line Jurkat, We further characterize the role forproto-oncogene c-maf, while, in leukemic T-cells and T-ALL patient, the T-cellspecific proto-oncoprotein c-Maf mediates a interchromosome interaction that bringsthe TAL1promoter1in close proximity with a novel T-cell specific DNA regulatoryelement located on chromosome16. This interaction is critical for ectopic TAL1expression in human T-cell leukemia.Here, we investigate the role of chromatin looping mechanisms along withhistone modification profiles, utilizing both candidate and genome-wide approachesin identification of novel enhancer elements that drive TAL1promoter in T-cell acutelymphoblastic leukemiaAltogether, our study reveals a novel molecular mechanism involving changes in three dimensional chromatin interactions underlying theactivation of the TAL1oncogene in human T-cell leukemia. Identification of a newTAL1interacting region in T-cell leukemia is of potential interest for future targetedstudies.