Our promise to you:
Guaranteed product quality, expert customer support.
Acute myeloid leukemia (AML) is a malignancy arising within the bone marrow, in which leukemia cells proliferate uncontrollably in association with disruption of normal hematopoiesis or blood cell production. Currently, the marrow of a patient with AML is occupied with approximately 1012 leukemia cells. Contributing factors to the low survival rates are the acuity and severity of illness at diagnosis. Patients with AML usually present because of complications of disordered hematopoiesis: fatigue, bleeding, refractory infections, or the clinical consequences of an extremely high white blood cell count: difficulty breathing, confusion, or other symptoms of organ failure. Previously incurable, AML is now cured in about 35%–40% of patients younger than age 60 years old. For those exceed 60 years old, the prognosis is improving but remains grim.
Emerging data gleaned with the use of new genomic techniques — in particular, next-generation sequencing — are providing an unparalleled view of the spectrum and frequency of mutations, their distinct patterns of cooperativity and mutual exclusivity, subclonal architecture, the clonal evolution during the disease course, and the epigenetic landscape of the disease. The Cancer Genome Atlas Research Network analyzed the genomes of 200 patients with AML. In this project, 23 genes were found to be recurrently mutated, including known genes such as CEBPA, DNMT3A, NPM1, FLT3, IDH1, and IDH2, and genes recently implicated in leukemogenesis, including U2AF1, SMC1A, EZH2, and SMC3. Although most genes were found to be mutant in one or two patients, there were nevertheless nonrandom mutational patterns of co-occurrence and mutual exclusivity. Mutations that are common in AML such as NPM1, CEPBA, and RUNX1 were mutually exclusive of transcription factor fusions, thereby supporting the notion that the mutations are leukemia-initiating events like the fusion genes. Moreover, mutual exclusivity was also found for mutations in genes encoding the cohesin factor complex, proteins of the spliceosome, and histone-modifying proteins.
Other important findings revealed by next generation sequencing studies relate to the pattern of mutation acquisition and the existence of preleukemic stem cells. Data from clonal evolution studies provide support for a model in which genes that are commonly involved in epigenetic regulation (i.e., DNMT3A, ASXL1, IDH2, and TET2) are present in preleukemic hematopoietic stem cells and occur early in the evolution of AML. Such ancestral preleukemic stem cells are capable of multiline age differentiation, can survive chemotherapy, and can expand during remission, eventually leading to relapse. Recent studies show that clonal hematopoiesis with somatic mutations, commonly involving the same genes (DNMT3A, TET2, and ASXL1), increases as people age and is associated with an increased risk of hematologic cancer and death. In absolute value, this risk is relatively low, and now it has no clinical consequences.
With the growing clinical translation of genomics into daily routine, AML has also become an important field for new drug investigation comprising the development of epigenetic modulators, protein kinase inhibitors, immune checkpoint inhibitors and cellular immunotherapies, mitochondrial inhibitors, and therapies that target specific oncogenic proteins and the AML microenvironment. Mutations in epigenetic modifiers, such as DNMT3A and IDH1/2, are commonly acquired earliest; successful inhibition of these genetic abnormalities may result in eradication of the founding clone. In contrast, mutations in receptor tyrosine kinase (eg, FLT3) or RAS pathway genes typically occur late; in many cases, their selective inhibition may address only a leukemia subclone, which leaves the antecedent clone present. These clonal relationships need to be taken into account when designing clinical trials with molecular targeted agents.
Creative Biogene, as a leading biotechnology company, can offer various AML pathway related products including stable cell lines, viral particles and clones for your pathogenesis study and drug discovery projects.