Characterization of p190-Bcr-Abl chronic myeloid leukemia reveals specific signaling pathways and therapeutic targets

Publikationen als Autor:in / Herausgeber:in der Vetmeduni

Mayer, Isabella; Sexl, Veronika; Doma, Eszter

Abstrakt

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.

Dokumententyp

Originalarbeit

Open Access Type

Hybrid

DOI

10.1038/s41375-020-01082-4

PubMed ID

MEDLINE:33168949