Large‐scale topological disruption of chromosome territories 9 and 22 is associated with nonresponse to treatment in CML. Issue 9 (29th December 2021) - Fabian‐Morales, Eunice
Abstract: Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm defined by the presence of t(9;22) translocation whose origin has been associated with the tridimensional genome organization. This rearrangement leads to the fusion of BCR and ABL1 genes giving rise to a chimeric protein with constitutive kinase activity. Imatinib, a tyrosine kinase inhibitor (TKI), is used as a first‐line treatment for CML, though ~40% of CML patients do not respond. Here, using structured illumination microscopy (SIM) and 3D reconstruction, we studied the 3D organization patterns of the ABL1 and BCR genes, and their chromosome territories (CTs) CT9 and CT22, in CD34+ cells from CML patients that responded or not to TKI. We found that TKI resistance in CML is associated with high levels of structural disruption of CT9 and CT22 in CD34+ cells, increased CT volumes (especially for CT22), intermingling between CT9 and CT22, and an open‐chromatin epigenetic mark in CT22. Altogether our results suggest that large‐scale disruption of CT9 and CT22 correlates with the clinical response of CML patients, which could be translated into a potential prognostic marker of response to treatment in this disease and provide novel insights into the mechanisms underlying resistance to TKI in CML. Abstract : What's new? The t(9;22) translocation and resulting encoding of a chimeric protein with constitutive tyrosine kinase activity is a hallmark of chronic myeloid leukaemia (CML). The genesis of this rearrangement is related to the topological organization of chromatin in the nucleus. Using super‐resolution microscopy, the authors studied the topological features of bone marrow stem cells from CML patients. They found that disruption of chromosome territories 9 and 22 associates with non‐response to tyrosine kinase inhibitors in CML. The results suggest a novel prognostic marker and provide new insights into the mechanisms underlying treatment resistance in CML and regulation of the 3D genome organization.