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

Shady Adnan-Awad,Soili Kytölä,Komal Kumar Javarappa,Satu Mustjoki,Helena Hohtari,Swapnil Potdar,Matti Kankainen,Caroline A Heckman,Daehong Kim,Eszter Doma,Isabella Mayer,Kimmo Porkka,Tania Brandstoetter,Veronika Sexl

doi:10.1038/s41375-020-01082-4

Abstract

The oncogenic protein Bcr-Abl has two major isoforms, p190Bcr-Abl and p210Bcr-Abl. While p210Bcr-Abl is the hallmark of chronic myeloid leukemia (CML), p190Bcr-Abl occurs in the majority of Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL) patients. In CML, p190Bcr-Abl occurs in a minority of patients associating with distinct hematological features and inferior outcomes, yet the pathogenic role of p190Bcr-Abl and potential targeting therapies are largely uncharacterized. We employed next generation sequencing, phospho-proteomic profiling, and drug sensitivity testing to characterize p190Bcr-Abl in CML and hematopoietic progenitor cell line models (Ba/f3 and HPC-LSK). p190Bcr-Abl CML patients demonstrated poor response to imatinib and frequent mutations in epigenetic modifiers genes. In contrast with p210Bcr-Abl, p190Bcr-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 p190Bcr-Abl CML patients, p190Bcr-Abl cell lines demonstrated similar transcriptional and phospho-signaling signatures. With the drug sensitivity screening we identified targeted drugs with specific activity in p190Bcr-Abl cell lines including IAP-, PAK1-, and Src inhibitors and glucocorticoids. Our results provide novel insights into the mechanisms underlying the distinct features of p190Bcr-Abl CML and promising therapeutic targets for this high-risk patient group.

Highlights

Presented in abstract form at the 61st annual meeting of the American Society of Hematology, Orlando, FL, 7 December 2019
Considering the drug sensitivity profiles of p190 and p210 cells, we investigated whether combining imatinib with other potentially useful drugs would enhance the inhibitory activity in p190 cells
Despite the signaling differences between p190 and p210 Bcr-Abl isoforms have been investigated in cell line models, the knowledge of the differences between these isoforms in primary leukemia cells, especially in chronic myeloid leukemia (CML), is still in infancy

Summary

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Presented in abstract form at the 61st annual meeting of the American Society of Hematology, Orlando, FL, 7 December 2019. The expression of p210 has been associated with slowly progressive CML-like disease while p190 is associated with short latency and acute Bcell leukemia, suggesting the contribution of Bcr-Abl isoforms to specific fates [18, 19]. Despite several studies have investigated the transcriptional activity and downstream signaling of Bcr-Abl, only a few studies have systematically compared the differences between p190 and p210 isoforms in uniform models. The drug sensitivity differences between both isoforms have not been systematically studied either with cell line models or primary cells of CML and Ph+ALL. Our study provides the first consolidated view of the molecular pathogenesis of p190-CML and identifies promising drug candidates which can be translated into tailored treatment strategies for these high-risk patients

Materials and methods

Results

Discussion

Findings

Compliance with ethical standards