Proteomic Profiling of Acute Promyelocytic Leukemia Identifies Two Protein Signatures Associated with Relapse.

PURPOSE: Acute promyelocytic leukemia (APL) is the most prognostically favorable subtype of Acute myeloid leukemia (AML). Defining the features that allow identification of APL patients likely to relapse after therapy remains challenging. EXPERIMENTAL DESIGN: Proteomic profiling is performed on 20 newly diagnosed APL, 205 non-APL AML, and 10 normal CD34+ samples using Reverse Phase Protein Arrays probed with 230 antibodies. RESULTS: Comparison between APL and non-APL AML samples identifies 8.3% of the proteins to be differentially expressed. Proteins higher expressed in APL are involved in the pro-apoptotic pathways or are linked to higher proliferation. The "MetaGalaxy" approach that considers proteins in relation to other assayed proteins stratifies the APL patients into two protein signatures. All of the relapse patients (n = 4/4) are in protein signature 2 (S2). Comparison of proteins between the signatures shows significant differences in relative expression for 38 proteins. Protein expression summary plots suggest less translational activity in combination with a less proliferative character for S2 compared to signature 1. CONCLUSIONS AND CLINICAL RELEVANCE: This study provides a potential proteomic-based classification of APL patients that may be useful for risk stratification and therapeutic guidance. Validation in a larger independent cohort is required.

MYC protein expression is an important prognostic factor in acute myeloid leukemia.

As new drugs targeting MYC show clinical activity in acute myeloid leukemia (AML), understanding MYC expression in AML is of critical importance. We assessed MYC protein expression by immunohistochemistry in bone marrow of patients with untreated AML (n = 265). Overall, 90% of patients demonstrated MYC overexpression and MYC immunopositivity ≤6% was associated with superior complete remission (CR) duration of 23 months versus 12 months for MYC immunopositivity >6% (p = .028). Among 241 patients at higher risk for relapse, including those ≥55 years of age and patients with intermediate- and high-risk AML, MYC immunopositivity ≤6% conferred significantly superior median overall survival (OS) (24 versus 13 months; p = .042), event-free survival (EFS) (14 versus 6 months; p = .048), and relapse-free survival (RFS) (25 versus 12 months; p = .024). The prognostic impact of MYC-immunopositivity was retained on multivariate analysis of OS, EFS, and RFS. We conclude that MYC immunopositivity is an important prognostic factor in patients with untreated AML, particularly those at higher risk for relapse.

Aberrant hnRNP K expression: All roads lead to cancer.

The classification of a gene as an oncogene or a tumor suppressor has been a staple of cancer biology for decades. However, as we delve deeper into the biology of these genes, this simple classification has become increasingly difficult for some. In the case of heterogeneous nuclear ribonuclear protein K (hnRNP K), its role as a tumor suppressor has recently been described in acute myeloid leukemia and demonstrated in a haploinsufficient mouse model. In contrast, data from other clinical correlation studies suggest that hnRNP K may be more fittingly described as an oncogene, due to its increased levels in a variety of malignancies. hnRNP K is a multifunctional protein that can regulate both oncogenic and tumor suppressive pathways through a bevy of chromatin-, DNA-, RNA-, and protein-mediated activates, suggesting its aberrant expression may have broad-reaching cellular impacts. In this review, we highlight our current understanding of hnRNP K, with particular emphasis on its apparently dichotomous roles in tumorigenesis.