Table 1.
Commonly mutated or aberrantly expressed genes in non-APL AML for which targeted drugs are being developed
| Mutated Gene | Gene pruduct function | Compound | Targets | trial phases | combinations | Trials Registered Clinicaltrials.gov (Nov 2012) | Refs |
|---|---|---|---|---|---|---|---|
| FLT3 | This gene encodes a tyrosine-protein kinase that acts as cell-surface receptor for the cytokine (fms-related tyrosine kinase 3 ligand) FLT3LG and regulates differentiation, proliferation and survival of hematopoietic progenitor cells and of dendritic cells. Activation of wild-type FLT3 causes only marginal activation of proliferation, and differentiation of hematopoietic cells in bone marrow. Mutations that cause constitutive kinase activity promote cell proliferation and resistance to apoptosis via the activation of multiple signaling pathways | Lestaurtinib | FLT3, JAK2 | 1,2,3 | chemotherapy | 4 active 4 completed | [89,211] |
| PLX3397 | FMS, KIT & FLT3 | 1 | none | 1 active | [96] | ||
| Quizartinib (AC220) | FLT3, KIT, PDGFRA, PDGFRB, RET | 1,2 | chemotherapy | 6 active 1 completed | [86] | ||
| Sorafenib | FLT3, cKIT | 1, 2 | 11 active 6 completed | [212-215] | |||
| Midostaurin | Multiple kinases | 1,2,3 | ATRA, Bortezomib, azacytidine, decitabine, chemotherapy | 9 active 4 completed | [90] | ||
| NPM1 | A nucleolar phosphoprotein that shuttles across cytoplasm and nucleus and regulates centrosome maturation and the ARF/p53 pathway. NPM1 leukemic mutants are characterized by insertions that cause a reading frame-shift and result in a longer protein with a different C-terminal, which is responsible for lossing the binding capacity to the nucleolus. This may contribute to leukemogenesis by inactivating p19Arf through delocalization of the tumor suppressor protein and dislocating NF-kappaB to the cytoplasm. | ATRA | Induces p53 and p21 | 1 | 2 active | [34] | |
| PLK1 | PLK1 is the most well characterized member of four serine/threonine protein kinases, which and strongly promotes the progression of cells through mitosis. PLK1 performs several important functions throughout M phase of the cell cycle, including the regulation of centrosome maturation and spindle assembly, the removal of cohesins from chromosome arms, the inactivation of anaphase-promoting complex/cyclosome (APC/C) inhibitors, and the regulation of mitotic exit and cytokinesis. It plays a key role in centrosome functions and the assembly of bipolar spindles. It als acts as a negative regulator of p53 family members leading to ubiquitination and subsequent degradation of p53/TP53, inhibition of the p73/TP73 mediated pro-apoptotic functions and phosphorylation/degradation of BORA. During the various stages of mitosis PLK1 localizes to the centrosomes, kinetochores and central spindle. Plk1 is found aberrantly overexpressed in a variety of human cancers and in AML, correlated with cellular proliferation and poor prognosis. | Volasertib | PLK1 | 1,2,3 | chemotherapy | 2 active | [216] |
| BI 2536 | PLK1 | 1,2 | chemotherapy | 1 completed | [207] | ||
| MLL | The MLL gene (mixed-lineage leukemia) encodes a protein plays an essential role in early development and hematopoiesis by acting as a histone methyltransferase and transcriptional co-activator. Among others it activates aberrant trascription DOT1L, which is considered a driver of leukemogenesis | EPZ-5676 | DOT1L | 1 | 1 active | [175] | |
| JAK2 | The Janus-kinase-2 gene (JAK2) encodes a non-receptor tyrosine kinase involved in relaying signals for hemopoietic cell growth, development and differentiation crossactivated by type I/II cytokine receptors | Ruxolitinib | JAK2 | 1,2 | 1 active | [217] | |
| Pacritinib | JAK2, FLT3 | 1 | 1 completed | [82] | |||
| Lestaurtinib (CEP-701) | JAK2, FLT3 | 1,2 | 1 active 3 completed | [218] |