HAP1 loss in L-asparaginase resistance

In this issue of Blood, Lee et al identify huntingtin associated protein 1 (HAP1) loss as a new marker of L-asparaginase resistance in acute lymphoblastic leukemia (ALL) and provide evidence for the pathway involved. They discovered that HAP1 is essential for the formation of the ternary complex with huntingtin (Htt) and inositol 1,4,5-triphosphate receptor (InsP3R) and that its loss impairs the L-asparaginase– mediated increase of cytosolic Ca21 needed for triggering apoptosis (see figure). Their data were confirmed by specific knockdown of HAP1 in SEM cells and by measurement of both endoplasmic reticulum–released Ca21 and external Ca21 influx.1