Towards new therapeutic strategies in t(4;11) leukemia

The current treatment of t(4;11) ALL is still correlated with poor outcome. Infant t(4;11) ALL is even worse. Thus, there is a medical need to improve the standard CTX or BMT. This can only been done with the molecular understanding of this disease entity. Here, we are following a therapeutic approach that has been brought up in two different laboratories (Barcelona and Frankfurt). The molecular targets are the KMT2A-AFF1 fusion protein and the Polycomb repressor complex II (PRC II) constituent EZH1/2. Both can be targeted by small molecules Entinostat and UNC1999, respectively. Entinostat is a selective HDAC class I inhibitor (HDAC 1-3) that disables KMT2A-AFF1 to bind to its target genes but enhances binding of wildtype KMT2A. UNC1999 inhibits the histone modifying enzymatic domain of EZH1/2, the key components of PRC II. The combination of both drugs enable chromatin modifications without targeting the biological activity of either KMT2A or AFF1 that are essential for living cells. We will present our data about single-agent or combined treatments in a t(4;11) model system and will discuss the potential consequences for future therapeutic interventions.

Publication History

Article published online:
09 May 2025