Characterizing the Role of TLX1 in T-cell Acute Lymphoblastic Leukemia
T-cell Acute Lymphoblastic Leukemias (T-ALLs) are aggressive hematological tumors caused by the aberrant expression of a subset of transcription factors (TFs) in T-cell progenitors1–3 . The identification of diverse sets of secondary mutations in T-ALL tumors suggests a complex process of clonal selection through which oncogenic TF-expressing pre-leukemic cells gradually transition along the path of oncogenic transformation3,4. While transgenic mouse studies have established the causative role of primary oncogenic TFs in driving leukemia, the mechanisms through which these proteins contribute to disease progression remain unclear. One subtype of T-ALL, representing 11% of T-ALL cases, is characterized by the translocation and ectopic expression of the homeobox family transcription factor TLX15–7 . TLX1 expression has been shown to stop thymocyte differentiation, dysregulate gene expression, and promote oncogenic transformation by accumulating genetic lesions and aneuploidy5,6,8–12. Characterization of TLX1 T-ALLs has suggested recurrent secondary mutations and colocalization with several transcription factors on the genome5,6,8,13. However, the precise mechanisms through which TLX1 transforms and maintains leukemic cells is currently unclear. To decipher the mechanism of oncogenic transformation in the TLX1 subtype of T-ALL, we used a multi-omics approach in complementary model systems to characterize changes in gene expression, epigenetics, chromatin accessibility, and 3D chromatin conformation at multiple stages of oncogenic transformation. TLX1 T-ALL human samples translocated TLX1 to the TCRδ locus and had diverse secondary mutations, and TLX1 strongly colocalized with the BAF complex and chromatin loop anchors. Our mouse model of TLX1 T-ALL revealed the transformation of pre-leukemic cells over many weeks and gradual progression to overt leukemias with diverse phenotypes and gene expression. Ectopic expression of TLX1 in thymocytes alters genome topology early in transformation, partly by recruitment of the BAF complex and induction of aberrant DNA topology via CTCF repositioning. Ectopic expression of TLX1 in the Jurkat T-ALL cell line altered chromatin looping, and acute loss of BAF complex function by inhibition or degradation killed the TLX1-expressing ALL-SIL cell line. Our results provide critical new insights into the molecular and cellular processes of leukemia transformation in TLX1 T-ALL and suggest a novel therapeutic approach through the disruption of chromatin remodeling factors.
TLX1, T-ALL, Leukemia, Epigenetics, Cancer Transformation, Chromatin conformation, T-cell Acute Lymphoblastic Leukemia, Gene regulation
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