More than one mutation is necessary to cause AML

It is plausible to determine risk through the analysis of molecular markers of disease. However, no single mutation or gene rearrangement appears to be sufficient for the development of therapy-related AML.

Several lines of evidence support the requirement for second mutations in leukemias associated with mutations of core binding factor (CBF), including analysis of the heritable FPD/ AML syndrome (familial platelet disorder with propensity to develop AML), the TEL/AML1 leukemias in syngeneic twins, and murine models of AML1/ETO and CBFP/MYH11 leukemias. In addition, point mutations that cause loss of function of AML1 have been identified in both inherited and sporadic leukemias. CBF is a heterodimeric transcription factor comprising AML1 (also known as RUNX1) and CBFP subunits. It is a common target of gene rearrangements as a consequence of chromosomal translocations, giving rise to the AML1/ETO, CBFPMYH11 and TEL/AML1 fusions. FPD/AML syndrome is an autosomal dominant trait characterized by a qualitative and quantitative platelet defect, progressive pancytopenia and dysplasia with age, and progression to AML associated with acquisition of secondary mutations. FPD/AML is caused by loss-of-function mutations in the AML1 gene, demonstrating that mutations in the AML1 component of CBF are not sufficient to cause leukemia, but require second mutations during the lifetime of affected individuals to cause leukemia. TEL/ AML1 leukemias have been studied in syngeneic twins, each of whom harbored the same clone of cells containing the TEL/ AML1 gene rearrangement at the time of birth, presumably as a result of intrauterine transmission of a TEL/AML1-positive clone. However, despite the syngeneic host background and the carriage of an identical TEL/AML1 clone, the twins devel

Secondary myelodysplasia/acute myelogenous leukemia—assessment of risk 49

oped leukemia at widely different ages, indicating the need for additional mutations to cause leukemia.

Murine models of leukemia also provide convincing evidence for 'multiple-hit' pathogenesis of disease. Expression of either AML1/ETO or CBF0/MYH11 fusion proteins alone in hematopoietic cells is not sufficient to cause leukemia, and chemical-induced mutagenesis must be added to generate a leukemia phenotype. Similar data emerge for PML/ RARa-mediated leukemias in transgenic murine models. PML/RARa is expressed in promyelocytes in the germline of transgenic animals under the control of the cathepsin G promoter. However, despite germline expression, animals require 4-6 months to develop leukemia and have karyotypically evident second mutations. Similarly, in MLL/AF9 knock-in mice there is a long latency required for the development of leukemia, and MLL/CBP leukemias in a murine bone marrow transplant model require long latencies, indicative of the need for second mutations.

Furthermore, leukemogenic fusions have been detected using sensitive PCR-based assays in normal individuals. Examples include IgH/BCL2, BCR/ABL, MLL tandem duplication and the TEL/AML1 fusion. The frequency of these rearrangements is much higher in the general population than the risk of developing the respective leukemias. These data indicate that carriage of even a known leukemogenic fusion gene does not provide useful information about the likelihood of progression to leukemia. Indeed, there are currently no data demonstrating that PCR-detectable fusions are a risk factor for the eventual development of leukemia. Collectively, these data indicate that the identification of a single gene rearrangement or point mutation may not necessarily be predictive of the development of therapy-related AML in the post-ASCT setting.

10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

Get My Free Ebook


Post a comment