Beyond ATP: asciminib and the allosteric path in CML

The authors demonstrated that the DNAbinding domain of BRD9 is not necessary for leukemogenic activity of BRD9-NUTM1, thus ruling out direct binding of the fusion protein to BRD9 targets.Notably, loss-of-function mutations in the p300 ortholog CREBBP are often detected in B-cell precursor ALL. 7An interesting possibility is that, in addition to the gain-of-function mechanism described by the authors, binding of p300 by the fusion protein depletes it from other areas of chromatin and DNA, thereby mimicking p300 loss-of-function.We have previously described such a combination of gainand loss-of-function for a similar p300binding fusion protein, ETV6-NCOA2, leading to T/myeloid leukemia. 8e second question concerns the striking difference in chemotherapy sensitivity between BRD4::NUTM1 NUT midline carcinoma and BRD9::NUTM1 pre-B ALL.Both cancers are highly proliferative and should depend on proper supply of nucleic acids.Could the tissue type be the reason for this difference?B cells and pre-B cells are more prone to apoptosis than epithelial cells, as many B cells die during differentiation due to nonproductive variable diversity joining rearrangements. 9It is tempting to speculate that this apoptosis prone phenotype underlies the dramatically better response of most B-cell precursor ALLs to chemotherapy compared with epithelial cancers, regardless of the rare NUTM1 rearrangements.