2015 – DISRUPTION OF CTCF BINDING BY THE ONCOGENIC TRANSCRIPTION FACTOR TLX1 ALTERS THE GENOMIC TOPOLOGY IN T CELL ACUTE LYMPHOBLASTIC LEUKEMIA (T-ALL).

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 progenitors. The identification of diverse sets of secondary mutations in T-ALL tumors suggest a complex process of clonal selection through which oncogenic TF-expressing pre-leukemic cells gradually transition along the path to oncogenic transformation. Whilst transgenic mice studies have established the causative role of oncogenic TFs in driving leukemia, the mechanism through which these proteins contribute to disease remains unclear. In particular, the role for epigenetic cofactors that mediate the oncogenic function of TFs remain unknown for most T-ALL subtypes.To decipher the mechanism of pre-leukemia to leukemia transition in the TLX1 subtype of T-ALL, we combined single cell genomic and proteomic approaches (CITEseq) with probability-based integrated analyses in time-course experiments across diverse stages of disease progression. These experiments identified the earliest leukemia-initiating cells in TLX1-type T-ALL, and revealed the trajectory taken by pre-leukemic cells that gradually progress along the path to become fully transformed blasts. At the mechanistic level, we showed ectopically expressed TLX1 disrupts genome topology through the recruitment of chromatin remodeling complexes and subsequent induction of aberrant DNA topology via CTCF repositioning. Consistent with this, we found that acute loss of chromatin remodeling proteins through PROTAC-based degradation selectively kills TLX1-expressing T-ALL blasts. Taken together, our results provide critical new insights into the molecular and cellular processes of leukemic transformation in T-ALL and suggest a novel therapeutic approach using genomic topology remodeling through PROTAC-based degradation of chromatin remodeling factors.