Transcriptional and functional heterogeneity of LICs in murine Setd2^−/−-AML was explored. Coexistence of two different types of LICs in this model brings about diverse chemo-response. Combined treatment with DA and RAS pathway inhibitors could kill both kinds of LICs and attenuate the disease progression. These findings may advance our understanding of the intra-heterogeneity of LICs and help us to develop more efficient treatments.

1. Mammalian FAM46C is a unique non-canonical poly(A) polymerase (PAP) with a bacterial-like protein fold.
2. FAM46C differs from its homolog FAM46B in PAP activity due to the divergence of amino acid residues at several critical sites.
3. The structural-functional characterization of MM-related FAM46C mutations that may be used for prognosis in the future.