Table 1.
Type of transformed cell and molecular pathways involved in leukemia pathogenesis
| Hematological disorders | Features | Molecular/chromosomal alterations | Global incidence (cases/ 100,000 inhabitants/year) | HECT E3s implicated in leukemia pathogenesis/progression |
|---|---|---|---|---|
| Acute myeloid leukemia (AML) |
A genetically very heterogeneous disorder characterized by the accumulation of acquired somatic mutations, epigenetic changes, chromosomal aberrations in hematopoietic progenitor cells that alter their self-renewal, proliferation, and differentiation |
Heterogeneity of molecular defects. Frequent somatic mutations include: NPM1, FLT3 and CEBPA, RUNX1, Somatic mutations in epigenetic modifiers include: DNMT3A, IDH1/2 and TET2 Cytogenetic abnormalities include: t(8;21), t(15;17), t(9;22) and inv(16) |
3,5 | WWP1 [42], HERC1 [94], E6AP [98, 99] |
| Chronic myelogenous leukemia (CML) | Clonal myeloproliferative disease characterized by leukocytosis and an accumulation of granulocytes and their precursors | The hallmark of CML is the (9;22)(q34;q11) reciprocal chromosomal translocation, leading to the constitutive expression of the fusion oncoprotein BCR–ABL | 1,5 | SMURF1 [56], HERC1 [94], |
| Acute lymphoblastic leukemia (ALL) | An aggressive hematological tumor, driven by malignant transformation and expansion of T-cell progenitors. It is the most common type of leukemia in children. ALL accounts for 74% of pediatric leukemia cases | One of the hallmarks of the disease is the Philadelphia chromosome positivity as a result of the t(9;22)(q34;q11). that gives rise to the BCR‐ABL oncogene. Philadelphia negative ALL are subcategorized on the basis of different classes of genetic alterations: type I, ABL‐class fusions; type II, erythropoietin‐receptor or JAK2 rearrangements; type III, cytokine receptor‐like factor 2 rearrangements; type IV, mutations activating JAK‐STAT signaling; type V, uncommon kinase mutations; type VI, RAS‐pathway mutations; type VII, no mutations in kinase genes | 1,8 | HERC1 [90–92] |
| Chronic lymphocytic leukemia (CLL) | A mature B cell neoplasm characterized by a progressive accumulation of monoclonal B lymphocytes |
More than forty mutated driver genes have been identified including NOTCH, FBXW7, KRAS, p53 and ATM Approximately 80% of CLL patients carry at least 1 of 4 common chromosomal alterations: del13q14, del11q22-23, del17p12, and trisomy 12 |
4,9 | ITCH [79], NEDD4 [86] |
| Myeloproliferative neoplasms (MPNs) |
Heterogenous group of acquired clonal hematopoietic stem cell disorders characterized by an abnormal proliferation of myeloid cells. MPNs include polycythemia vera, essential thrombocythemia, and primary (idiopathic) myelofibrosis. MPN patients can spontaneously transform into either myelodysplastic syndrome or AML |
Somatic mutations (JAK2, calreticulin, thrombopoietin receptor | 2,17 | HERC1 [94] |