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Deletion of Abl's N\u2010terminal region, to which myristoyl is linked, renders the Bcr\u2010Abl fusion oncoprotein constitutively active. The substitution of Abl's N\u2010terminal region by Bcr enables Bcr\u2010Abl oligomerization. Oligomerization is critical: it promotes clustering on the membrane, which is essential for potent MAPK signaling and cell proliferation. Here we decipher the Bcr\u2010Abl specific, step\u2010by\u2010step oligomerization process, identify a specific packing surface, determine exactly how the process is structured and identify its key elements. Bcr's coiled coil (CC) domain at the N\u2010terminal controls Bcr\u2010Abl oligomerization. Crystallography validated oligomerization via Bcr\u2010Abl dimerization between two Bcr CC domains, with tetramerization via tight packing between two binary assemblies. However, the structural principles guiding Bcr CC domain oligomerization are unknown, hindering mechanistic understanding and drugs exploiting it. Using molecular dynamics (MD) simulations, we determine that the binary complex of the Bcr CC domain serves as a basic unit in the quaternary complex providing a specific surface for dimer\u2013dimer packing and higher\u2010order oligomerization. We discover that the small \u03b11\u2010helix is the key. In the binary assembly, the helix forms interchain aromatic dimeric packing, and in the quaternary assembly, it contributes to the specific dimer\u2013dimer packing. Our mechanism is supported by the experimental literature. It offers the key elements controlling this process which can expand the drug discovery strategy, including by Bcr CC\u2010derived peptides, and candidate residues for small covalent drugs, toward quenching oligomerization, supplementing competitive and allosteric tyrosine kinase inhibitors.<\/jats:p>","DOI":"10.1002\/pro.4504","type":"journal-article","created":{"date-parts":[[2022,11,12]],"date-time":"2022-11-12T05:15:59Z","timestamp":1668230159000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Higher\u2010order interactions of <scp>Bcr\u2010Abl<\/scp> can broaden chronic myeloid leukemia (CML) drug repertoire"],"prefix":"10.1002","volume":"32","author":[{"given":"Yonglan","family":"Liu","sequence":"first","affiliation":[{"name":"Cancer Innovation Laboratory National Cancer Institute  Frederick Maryland 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