Chemico-genetic strategies to inhibit the leukemic potential of threonine aspartase-1
Chromosomal rearrangements of the mixed lineage leukemia (MLL) gene with numerous partner genes are frequently found in acute myeloid (AML) and acute lymphoblastic leukemia (ALL). Although the pathomechanism of t(4;11)-mediated leukemia is still discussed, expression of the AF4•MLL fusion enhanced the repopulating potential of CD34+-cells, and led to the development of predominantly proB-ALL in a mouse model. The AF4•MLL protein contains cleavage-sites for Threonine Aspartase-1 (Taspase1). Upon processing by Taspase1, the AF4•MLL cleavage products form a protein complex resistant to SIAH-mediated degradation and activate oncogenic programs. Furthermore, Taspase1 is overexpressed in liquid and solid human cancers suggesting that Taspase1 is coopted to promote and sustain tumorigenesis. As genetic deletion of Taspase1 in the mouse produced no overt deﬁciencies, inhibition of Taspase1 may offer novel anticancer strategies, including the treatment of leukemias. Human Taspase1 encodes a protease of 420 amino acids (aa) cleaving substrates in trans by recognizing a conserved peptide motif (Q3[F,I,L,V]2D1↓G1’x2’D3’D4’). Unfortunately, Taspase1’s activity is not affected by common protease inhibitors, currently precluding the assessment of its clinical and therapeutic relevance. Here, we present our endeavors to target Taspase1’s oncogenic potential by (i) overexpression of inactive Taspase1 variants, and (ii) testing a putative Taspase1 inhibitor.