The Progression of Acute Myeloid Leukemia from First Diagnosis to Chemoresistant Relapse: A Comparison of Proteomic and Phosphoproteomic Profiles

Abstract

Acute myeloid leukemia (AML) is an aggressive hematological malignancy. Nearly 50% of the patients who receive the most intensive treatment develop chemoresistant leukemia relapse. Although the leukemogenic events leading to relapse seem to differ between patients (i.e., regrowth from a clone detected at first diagnosis, progression from the original leukemic or preleukemic stem cells), a common characteristic of relapsed AML is increased chemoresistance. The aim of the present study was to investigate at the proteomic level whether leukemic cells from relapsed patients present overlapping molecular mechanisms that contribute to this chemoresistance. We used liquid chromatography–tandem mass spectrometry (LC–MS/MS) to compare the proteomic and phosphoproteomic profiles of AML cells derived from seven patients at the time of first diagnosis and at first relapse. At the time of first relapse, AML cells were characterized by increased levels of proteins important for various mitochondrial functions, such as mitochondrial ribosomal subunit proteins (MRPL21, MRPS37) and proteins for RNA processing (DHX37, RNA helicase; RPP40, ribonuclease P component), DNA repair (ERCC3, DNA repair factor IIH helicase; GTF2F1, general transcription factor), and cyclin-dependent kinase (CDK) activity. The levels of several cytoskeletal proteins (MYH14/MYL6/MYL12A, myosin chains; VCL, vinculin) as well as of proteins involved in vesicular trafficking/secretion and cell adhesion (ITGAX, integrin alpha-X; CD36, platelet glycoprotein 4; SLC2A3, solute carrier family 2) were decreased in relapsed cells. Our study introduces new targetable proteins that might direct therapeutic strategies to decrease chemoresistance in relapsed AML.

Inhibition of NF-κB Signaling Alters Acute Myelogenous Leukemia Cell Transcriptomics

“…Second, another subset of genes encoded proteins that are important for mitochondrial functions, and thereby, probably also for the regulation of cellular metabolism. The targeting of mitochondria or cellular metabolism is now regarded as a possible therapeutic strategy in human AML [ 48 , 49 , 50 , 51 ]. Third, several downregulated genes encoded interacting proteins that are important for the spliceosome or RNA binding/transport.…”

The Implementation of Mass Spectrometry-Based Proteomics Workflows in Clinical Routines of Acute Myeloid Leukemia: Applicability and Perspectives

“…AML is a very heterogeneous disease and this heterogeneity has been demonstrated both by cytogenetic and molecular genetic analyses as well as gene expression, epigenetic, and possibly also proteomic and metabolic profiling [ 12 , 43 , 44 , 45 , 46 , 47 , 48 ]. The most important factors for evaluation of AML relapse risk in routine clinical practice are the cytogenetic and the molecular genetic abnormalities (these and other prognostic factors are gathered in Table 1 ).…”

“…First, early morphological disease control with remission induction (but remaining MRD) is an important prognostic parameter [ 13 , 14 , 73 , 74 ] and this is a characteristic of the total AML cell population. Second, a large number of clinical studies have shown that biological characteristics of the total AML cell population reflect fundamental cell population characteristics that have a prognostic impact and are essential for leukemogenesis/chemosensitivity [ 43 , 44 , 46 , 47 , 48 ]. Third, previous studies have shown that the AML stem cells can be detected in various subsets, usually CD34 + CD38 − but also CD34 − and CD34 + CD38 + cells [ 65 , 75 , 76 ].…”

“…In another recent study, we compared proteomic and phosphoproteomic profiles for paired AML cell samples derived at the time of primary diagnosis and later, after completed intensive chemotherapy, at the time of the first relapse from the same patients [ 47 ]. Interestingly, the high CDK activity detected at diagnosis for patients who later relapsed was also observed in chemoresistant cells after relapse.…”

Comment on Aasebø, E., et al. “The Progression of Acute Myeloid Leukemia from First Diagnosis to Chemoresistant Relapse: A Comparison of Proteomic and Phosphoproteomic Profiles”. Cancers 2020, 12, 1466

“…In a recent article published in this journal, Aasebø and colleagues reported [ 1 ] increased levels of various proteins, including CD36, in acute myeloid leukemia (AML) cells at relapse, when compared with the time of first presentation, and suggest targeting these proteins for direct therapeutic strategies to alleviate chemoresistance in relapsed AML. Interestingly, CD36 is a scavenger receptor that mediates lipid uptake, and is gaining attention in clinical trials as a potential druggable target in cancer treatment [ 2 ].…”