LICs Of APL-Like Leukemia Lead a Step-Wise and Divergent Differentiation Course

The differentiation of leukemia-initiating cells (LICs) is generally regarded as a one-way alterative process to self-renewal. However, how differentiation impacts the leukemic stemness is largely unexplored. Here we show that a top tier of undifferentiated (UD), and a medium tier of partially differentiated (PD) LICs coexist within a PML/RARa-expressing mouse leukemia model. PD-LICs not only self-renew or even de-differentiate, but also mature into terminally differentiated (TD) monocytic or granulocytic non-LICs. Notably, PD-LICs but not UD-LICs were partially refractory to the differentiation-inducing effect of ATRA, a cognate ligand of PML/RARa. Nevertheless, the upregulation of monocytic transcriptional factor Irf8, albeit being dampened by RA signaling, relieves the differentiation arrest of most PD-LICs. Thus, our study reveals a sequential and divergent differentiation course of PML/RARa-expressing LICs under the regulation of discrete stage- and lineage- specific mechanisms.