Characterization of p190-Bcr-Abl chronic myeloid leukemia reveals specific signaling pathways and therapeutic targets
Shady Adnan Awad, Daehong Kim, Helena Hohtari, Komal Kumar Javarappa, Tania Brandstoetter, Isabella Maria Mayer, Swapnil Potdar, Caroline A. Heckman, Soili Kytölä, Kimmo Porkka, Eszter Doma, Veronika Sexl, Matti Kankainen, Satu Mustjoki
Abstract
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.