Abstract
Acute myeloid leukemia (AML) is a hematological cancer that mainly affects the elderly. Although complete remission (CR) is achieved for the majority of the patients after induction and consolidation therapies, nearly two-thirds relapse within a short interval. Understanding biological factors that determine relapse has become of major clinical interest in AML. We utilized liquid chromatography tandem mass spectrometry (LC-MS/MS) to identify the protein changes and protein phosphorylation events associated with AML relapse in primary cells from 41 AML patients at time of diagnosis. Patients were defined as relapse-free if they had not relapsed within a five-year clinical follow-up after AML diagnosis. Relapse was associated with increased expression of RNA processing proteins and decreased expression of V-ATPase proteins. We also observed an increase in phosphorylation events catalyzed by cyclin-dependent kinases (CDKs) and casein kinase 2 (CSK2). The biological relevance of the proteome findings was supported by cell proliferation assays using inhibitors of V-ATPase (bafilomycin), CSK2 (CX-4945), CDK4/6 (abemaciclib) and CDK2/7/9 (SNS-032). While bafilomycin preferentially inhibited the cells from relapse patients, the kinase inhibitors were less efficient in these cells. This suggests that therapy against the upregulated kinases could also target the factors inducing their upregulation rather than their activity. This study, therefore, presents markers that could help predict AML relapse and direct therapeutic strategies.
Highlights
Acute myeloid leukemia (AML) is an aggressive and heterogeneous malignancy, the two main subsets being acute promyelocytic leukemia (APL) and the heterogenous group non-APL AML [1,2].The APL variant is described by a characteristic clinical picture, specific cytogenetic abnormalities, different treatment than the other non-APL variants and a favorable prognosis [3]
The main characteristics of our patient cohort are given in Table patients); the most common mutations were on NPM1 and FLT3-ITD (Table S1)
We found a strong bias towards acidic amino acids such as glutamic acid (E), in close proximity to the differentially phosphorylated sites in the RELAPSE group when compared to the unregulated phosphosites (Figure S6a), suggesting a higher casein kinase 2 (CSK2) activity in this group
Summary
Acute myeloid leukemia (AML) is an aggressive and heterogeneous malignancy, the two main subsets being acute promyelocytic leukemia (APL) and the heterogenous group non-APL AML [1,2].The APL variant is described by a characteristic clinical picture, specific cytogenetic abnormalities, different treatment than the other non-APL variants and a favorable prognosis [3]. We will use the term AML to refer to the non-APL variants of the disease, and these variants are highly heterogeneous regarding genetic abnormalities and prognosis (i.e., relapse-free survival), with a median age at the time of first diagnosis of 65–70 years [4]. Despite the heterogeneity of the non-APL variants, these patients are treated according to the same guidelines, both with regard to intensive and potentially curative treatment (possibly including stem cell transplantation) for the young and fit subset of patients and less intensive leukemia-stabilizing treatment for elderly (i.e., above 70–74 years of age) or unfit patients [4,5,6]. There is a need for a better prognostic classification and therapeutic strategies both for the younger patients receiving intensive therapy and for the large majority of elderly or unfit patients receiving leukemia-stabilizing therapy
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