**Abstract**

Acute leukemia are a heterogeneous group of malignant diseases of the bone marrow that occur at all ages. Acute lymphoid leukemia (ALL) accounts for about 80% of all pediatric leukemia patients, whereas acute myeloid leukemia (AML) is more common in adults compared to pediatric patients. Despite similar patterns in the pathogenesis of acute leukemia in children and adults, clinical outcome in response to therapy differs substantially. Studying proteoforms in acute leukemia in children and adults, might identify similarities and differences in crucial signaling pathways that play a key role in the development or progression of the disease. In this chapter we will discuss how the study of proteoforms in acute leukemia could potentially contribute to a better understanding of the leukemogenesis, can help to identify effective targets for specific targeted treatment approaches in different subgroups of age and disease, and could aid the development of reliable biomarkers for prognostic stratification.

**Keywords:** acute myeloid leukemia, acute lymphoblastic leukemia, proteoforms, RPPA, pediatrics

### **1. Introduction**

Acute leukemia forms a group of rapidly progressing malignant diseases characterized by a block in the differentiation and an uncontrolled clonal proliferation of abnormal hematopoietic progenitor cells in the bone marrow and the peripheral blood [1, 2]. This accumulation of immature cells ("blasts") interferes with the production of normal blood cells, causing neutropenia, thrombocytopenia and anemia. According to the lineage of origin of the progenitor cells, the common lymphoid or the common myeloid, acute leukemia can roughly be classified into acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).

Acute leukemia patients are diagnosed using morphologic, cytochemical and immunophenotypic methods, and are further sub-classified by chromosomal analysis and the presence or absence of somatically acquired gene mutations. While classification allows for prediction of outcome, the outcome risk of a large group of patients is still difficult to define. In addition, treatment options are expanding that treat patients based on their genetic abnormalities (in particular in the adult population), but so far most genetic abnormalities are not yet targetable, and most

drugs that enter clinical trials rely on the increased abundance or altered activity of proteins, namely specific proteoforms, instead of the genetic lesion itself.

Proteoforms are defined as different forms of a protein derived from a single gene, and include all forms of genetic variation (e.g. amino acid variation), alternative splicing, and post-translational modifications (PTM). This means that one transcribed gene can lead to a variety of protein structures, and that the biological function of the final proteoform, as well as the cellular localization, binding partners and kinetics can vary greatly. As this suggests that gene sequences do not accurately predict the expression of a protein or whether the protein is stable or functional, it is not surprising that transcriptome data only correlates for about 17–40% with protein abundance [3–5]. Proteoforms are the basic units of a proteome. We believe that the study of proteoforms is an essential strategy to reveal cell dependencies and their underlying mechanism, and that this could add in the process of risk stratification and could identify novel therapeutic targets in highly complex diseases such as acute leukemia. Moreover, as the cure rates between ALL and AML, and between children and adults markedly differ, a direct comparison of the leukemic proteoforms between those patients, may aid to unravel the biological pathogenesis, and reveal similarities and dissimilarities that can propose therapeutics that target these proteoforms in one disease, that could also be effective in an otherwise disparate leukemia that shares protein patterns.
