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While p210<jats:sup>Bcr-Abl<\/jats:sup>is the hallmark of chronic myeloid leukemia (CML), p190<jats:sup>Bcr-Abl<\/jats:sup>occurs in the majority of Philadelphia-positive acute lymphoblastic leukemia (Ph\u2009+\u2009ALL) patients. In CML, p190<jats:sup>Bcr-Abl<\/jats:sup>occurs in a minority of patients associating with distinct hematological features and inferior outcomes, yet the pathogenic role of p190<jats:sup>Bcr-Abl<\/jats:sup>and potential targeting therapies are largely uncharacterized. We employed next generation sequencing, phospho-proteomic profiling, and drug sensitivity testing to characterize p190<jats:sup>Bcr-Abl<\/jats:sup>in CML and hematopoietic progenitor cell line models (Ba\/f3 and HPC-LSK). p190<jats:sup>Bcr-Abl<\/jats:sup>CML patients demonstrated poor response to imatinib and frequent mutations in epigenetic modifiers genes. In contrast with p210<jats:sup>Bcr-Abl<\/jats:sup>, p190<jats:sup>Bcr-Abl<\/jats:sup>exhibited specific transcriptional upregulation of interferon, interleukin-1 receptor, and P53 signaling pathways, associated with hyperphosphorylation of relevant signaling molecules including JAK1\/STAT1 and PAK1 in addition to Src hyperphosphorylation. Comparable to p190<jats:sup>Bcr-Abl<\/jats:sup>CML patients, p190<jats:sup>Bcr-Abl<\/jats:sup>cell lines demonstrated similar transcriptional and phospho-signaling signatures. With the drug sensitivity screening we identified targeted drugs with specific activity in p190<jats:sup>Bcr-Abl<\/jats:sup>cell lines including IAP-, PAK1-, and Src inhibitors and glucocorticoids. Our results provide novel insights into the mechanisms underlying the distinct features of p190<jats:sup>Bcr-Abl<\/jats:sup>CML and promising therapeutic targets for this high-risk patient group.<\/jats:p>","DOI":"10.1038\/s41375-020-01082-4","type":"journal-article","created":{"date-parts":[[2020,11,9]],"date-time":"2020-11-09T18:06:14Z","timestamp":1604945174000},"page":"1964-1975","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":61,"title":["Characterization of p190-Bcr-Abl chronic myeloid leukemia reveals specific signaling pathways and therapeutic targets"],"prefix":"10.1038","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6205-7799","authenticated-orcid":false,"given":"Shady","family":"Adnan-Awad","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1253-8946","authenticated-orcid":false,"given":"Daehong","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1510-8319","authenticated-orcid":false,"given":"Helena","family":"Hohtari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Komal Kumar","family":"Javarappa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4037-5352","authenticated-orcid":false,"given":"Tania","family":"Brandstoetter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella","family":"Mayer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2778-6918","authenticated-orcid":false,"given":"Swapnil","family":"Potdar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline A.","family":"Heckman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soili","family":"Kyt\u00f6l\u00e4","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimmo","family":"Porkka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eszter","family":"Doma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronika","family":"Sexl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4714-9481","authenticated-orcid":false,"given":"Matti","family":"Kankainen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0816-8241","authenticated-orcid":false,"given":"Satu","family":"Mustjoki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,11,9]]},"reference":[{"key":"1082_CR1","doi-asserted-by":"crossref","first-page":"8652","DOI":"10.1038\/sj.onc.1206094","volume":"21","author":"F Pane","year":"2002","unstructured":"Pane F, Intrieri M, Quintarelli C, Izzo B, Muccioli GC, Salvatore F. 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SM has received honoraria and research funding from Novartis, Pfizer, and Bristol-Myers Squibb (not related to this study). SAA and HH have received research funding from Incyte.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}