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Adnan-Awad, Shady; Kim, Daehong; Hohtari, Helena; Javarappa, Komal Kumar; Brandstoetter, Tania; Mayer, Isabella; Potdar, Swapnil; Heckman, Caroline A; Kytola, Soili; Porkka, Kimmo; Doma, Eszter; Sexl, Veronika; Kankainen, Matti; Mustjoki, Satu
Leukemia, 07/2021, Letnik: 35, Številka: 7Journal Article
Abstract The oncogenic protein Bcr-Abl has two major isoforms, p190 Bcr-Abl and p210 Bcr-Abl . While p210 Bcr-Abl is the hallmark of chronic myeloid leukemia (CML), p190 Bcr-Abl occurs in the majority of Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL) patients. In CML, p190 Bcr-Abl occurs in a minority of patients associating with distinct hematological features and inferior outcomes, yet the pathogenic role of p190 Bcr-Abl and potential targeting therapies are largely uncharacterized. We employed next generation sequencing, phospho-proteomic profiling, and drug sensitivity testing to characterize p190 Bcr-Abl in CML and hematopoietic progenitor cell line models (Ba/f3 and HPC-LSK). p190 Bcr-Abl CML patients demonstrated poor response to imatinib and frequent mutations in epigenetic modifiers genes. In contrast with p210 Bcr-Abl , p190 Bcr-Abl 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 Bcr-Abl CML patients, p190 Bcr-Abl cell lines demonstrated similar transcriptional and phospho-signaling signatures. With the drug sensitivity screening we identified targeted drugs with specific activity in p190 Bcr-Abl cell lines including IAP-, PAK1-, and Src inhibitors and glucocorticoids. Our results provide novel insights into the mechanisms underlying the distinct features of p190 Bcr-Abl CML and promising therapeutic targets for this high-risk patient group.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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