*2.1.2 Prognosis*

*Proteoforms - Concept and Applications in Medical Sciences*

otherwise disparate leukemia that shares protein patterns.

occurs in 5–6% of the ALL patients, independent of age.

**2. Acute leukemia**

**2.1 Acute lymphoblastic leukemia**

above the age of 50 years [6].

*2.1.1 Cytogenetic abnormalities*

drugs that enter clinical trials rely on the increased abundance or altered activity of

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

ALLs are neoplasms composed of immature B (pre-B), T (pre-T) or NK-cells that are referred as ("lymphoblasts"), of which the majority is pre-B ALL (85–90% in children vs. 75% in adults) [1]. It is the most common cancer in children and accounts for a quarter of all childhood malignancies. Although there are as many adults with ALL as there are children with the disease, the relative frequency in adults is much lower. Worldwide, the overall incidence is approximately 1–2 per 100.000 people, with a peak incidence occurring in childhood and a second peak

Chromosomal aberrations are the hallmark of ALL and are often used to categorize patients. In B-ALL, recurrent chromosomal abnormalities are found in 80% of the patients, including numerical and structural changes as translocations, deletions and inversions. There are substantial differences in the frequencies of occurring of cytogenetic abnormalities between children and adults [1, 7–10]. For instance, the translocation 9;22 [*BCR-ABL1*] is observed in 2–5% of the children compared to in 30% of the adults, whereas the translation 12;21 [*ETV6-RUNX1*] is observed in 25% of the pediatric patients versus 3% in adult population. The hyperdiploid (gain of chromosomes) karyotype is present in 30–40% of the children compared to 3% in adults. Finally, translocation 4;11 resulting in the MLL-AF4 fusion gene, is detected in 60–80% of the infants (younger than 1 year old), whereas it is seen in only 2% of the patients up to 15 years and rare in adults. Hypodiploidy (loss of chromosomes)

Chromosomal translations occur less frequently in T-ALL compared to B-ALL (approximately 50–60%) and unlike in B-ALL their prognostic impact is not well defined and they are not used for risk stratification [10]. They are involved in both

proteins, namely specific proteoforms, instead of the genetic lesion itself.

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Survival in children with ALL is much better compared to adults, with the exception of infant ALL. In 60–80% of the cases, infant ALL is characterized by translocations involving 11q23, affecting the KMT2A gene. Aberrant KMT2A in ALL is associated with a high rate of early treatment failure and a very poor outcome (long-term event-free survival of 28–45%), even when treated with more aggressive chemotherapy regimens [11, 12]. Historically, pediatric T-ALL was considered as high-risk disease. With the introduction of therapy intensification in T-cell ALL, this has changed to outcomes comparable to B-cell ALL, resulting in a five-year OS rate of more than 90% [13]. However, within certain high-risk subgroups (e.g. infants or children ≥10 years of age), 25–30% still experience relapse, which has a dismal outcome even with hematopoietic stem cell transplantation. Death resulting from treatment toxicity remains a challenge with an estimated 10-year cumulative incidence of treatment-related death of 2.9% [14].

Survival for ALL in adults is around 45%, but patients above the age of 60 suffer from inferior outcomes with only 10–15% long-term survival [10]. This is, at least partially, due to higher risk of medical comorbidities, the inability to tolerate standard chemotherapy regimens, and age-related unfavorable intrinsic biology such as Philadelphia chromosome positive, hypodiploidy and complex karyotype. However, as even the adolescents and young adults who lack medical comorbidities do significantly worse compared to their younger counterparts, the contribution of the different underlying biology should not be underestimated [8].
