Risk Of t-AML Research Articles

Polymorphisms in human homeobox HLX1 and DNA repair RAD51 genes increase the risk of therapy-related acute myeloid leukemia

AbstractStudies of radiation-induced acute myeloid leukemia (AML) in mice suggest that the number of target stem cells is a risk factor, and the HLX1 homeobox gene, which is important for hematopoietic development, is a candidate gene. The distribution of the C/T-3′ untranslated region (UTR) polymorphism in HLX1 in patients with AML and therapy-related AML (t-AML) compared with controls was therefore determined. The presence of the variant HLX1 allele significantly increases the risk of t-AML (OR = 3.36, 95% CI, 1.65-6.84). The DNA repair gene RAD51 (135G/C-5′ UTR) polymorphism also increases t-AML risk, and when combined analysis was performed on both RAD51 and HLX1 variant alleles, a synergistic 9.5-fold increase (95% CI, 2.22-40.64) in the risk of t-AML was observed. We suggest that the HLX1 polymorphism has an effect on stem cell numbers, whereas an increased DNA repair capacity (RAD51) will suppress apoptosis, a genetic interaction that may increase the number of genomes at risk during cancer therapy.

Polymorphisms in Human Homeobox HLX1 and DNA Repair RAD51 Genes Increase the Risk of Therapy-Related Acute Myeloid Leukemia.

It is generally accepted that genetic low penetrance susceptibility and resistance genes within the general population make a significant contribution to therapy-related acute myeloid leukaemia (t-AML) risk. The risk of malignant transformation is defined by the number of mutations required and the mutation rate, but one additional theoretical risk factor is the target cell frequency, as this defines the number of genomes at risk. Whilst the genetic control of target cell frequency is unknown in humans, a leading candidate gene is the HLX1 homeobox transcription factor gene. HLX1 is specifically expressed on CD34+ cells and plays a vital role in hemopoietic development. In addition the HLX1 gene lies within a proposed human t-AML susceptibility locus on chromosome 1, as defined by murine radiation-induced AML genetic studies. We have examined the distribution of a C/T-3′UTR polymorphism in HLX1 in 189 AML patients, including 42 cases of t-AML, and 169 control subjects. The presence of a variant HLX1-3′UTR T allele resulted in a significant increase in the risk of t-AML (OR= 3.36, 95% CI 1.65–6.84); to our knowledge, this is the first time that a gene which is implicated in target cell biology has been associated with an increased risk of malignant transformation. In addition we examined polymorphisms in genes involved in DNA repair (RAD51 and XRCC2), carcinogen detoxification (HYL1) and methionine metabolism (MTHFR and MS). There was no difference in the distribution of the XRCC2, HYL1, MTHFR or MS polymorphisms in the control and AML cohorts studied. The RAD51 homologous recombination DNA repair gene polymorphism (135G/C-5′UTR) has been shown to result in enhanced promoter activity with consequent elevated mRNA expression and this polymorphism has previously been demonstrated to increase t-AML risk (OR=2.66, 95% CI 1.17–6.02). When combined analysis was performed on RAD51 (135G/C- 5′ UTR) and HLX1 (C/T -3′UTR) a 9.5-fold increase in the risk of t-AML was associated with the presence of variant alleles of both genes (OR= 9.50, 95% CI 2.22–40.64). The synergistic genetic interaction between the HLX1-C/T (3′- UTR) and RAD51-135 G/C polymorphisms demonstrates that target cell biology together with an increased homologous recombination DNA repair capacity, significantly increases the risk of t-AML. We suggest that this is because the HLX1-C/T (3′- UTR) polymorphism results in a higher number of stem cells; hence during genotoxic therapy (for a primary malignancy) there is an increased target cell number for genotoxic damage and potential malignant transformation. An optimum repair system is necessary to ‘deal' with this burden of repair, however, the presence of altered repair capacity due to the RAD51-135C/T polymorphism may result in mis-repair and together with lack of apoptosis (due to a over-efficient repair system) will encourage the perpetuation of the oncogenic transformation and AML susceptibility.

Pharmacogenetics of Alkylator-Associated Acute Myeloid Leukemia

Therapy-related acute myeloid leukemia (t-AML) is a lethal late complication of alkylator chemotherapy. The genetic basis of susceptibility to t-AML is poorly understood. Both t-AML and de novo AML are complex genetic diseases, requiring cooperating mutations in interacting pathways for disease initiation and progression. Germline variants of these 'leukemia pathway' genes may cooperate with somatic mutations to induce both de novo and therapy-related AML. Several cancer susceptibility syndromes have been identified that cause an inherited predisposition to de novo and t-AML. The genes responsible for these syndromes are also somatically mutated in sporadic AML. We reason that germline polymorphism in any gene somatically mutated in AML could contribute to t-AML risk in the general population. Identification of these susceptibility alleles should help clinicians develop tailored therapies that reduce the relative risk of t-AML.

Treatment-Related Acute Myeloid Leukemia Following Therapy for Acute Myeloid Leukemia.

More than 50% of patients (pts.) who relapse from Acute Myeloid Leukemia (AML) have karyotypes different from those seen at primary diagnosis. This phenomenon might mirror clonal evolution or might result from antecedent therapies. In some cases completely different karyotypes might characterize treatment-related AML (t-AML). t-AML is a well recognized complication following treatment of malignancies with a high cure rate, especially primary breast cancer and Hodgkin's Disease and, according to a recently increasing number of reports, even in Acute Promyelocytic Leukemia. However, as to our knowledge there are no data from larger series concerning therapy-induced AML following chemotherapy for AML also comprising Non-M3-AML. Furthermore we asked if polymorphisms in phase-II-enzymes like Gluthathione S-Transferase (GST) or N-Acetyl-Transferase (NAT) might be risk factors for t-AML. Cytogenetics of 141 (72 male, 69 female) pts. who were presumed to have relapsed from AML on the basis of cytologic criteria were performed. In 99 of them cytogenetic data from initial diagnosis could be made available and were compared to the corresponding results on relapse. Six classes of cytogenetic sequences (initial diagnosis --> relapse) were defined (normal --> normal: 29 pts; normal --> aberrant: 16 pts.; aberrant --> aberrant with identical aberrations: 22 pts.; aberrant --> aberrant with additional anomalies: 19 pts.; aberrant --> aberrant with completely different anomalies: 7pts.; aberrant --> normal: 6 pts.) to characterize the dynamics of genetics from diagnosis to relapse. Among the 7 pts. who developed completely different anomalies from those seen at initial diagnosis 2 had cytogenetic anomalies characteristic for those seen following treatment with alkylating agents, while the aberrations in the remaining pts. fitted neither those typical for alkylating agents nor those for the topoisomerase-II-inhibitor type of treatment related anomalies. Of the 35 pts. in the second and third group together 3 pts. presented chromosomal changes of alkylating agents' type, 2 of topoisomerase-II-inhibitors' type, 1 patient a combination of both and in the remaining pts. such aberrations that could not be related to defined groups of chemotherapeutics so far. As far as available data from bone marrow smears, immunophenotyping, Fluorescence-In-Situ-Hybridization and moleculargenetics were used to differentiate clonal evolution from the development of a chemotherapy induced new clone. We conclude that a small proportion (6,93%) of seemingly relapsed AMLs might be treatment related, thus representing new clonal hematologic disorders completely different from the initial disease. Cytogenetic aberrations characteristic of alkylating drugs arose in pts. some of whom never received alkylating agents and at time intervals shorter than those supposed to be characteristic of t-AML following this class of drugs. Perhaps further types of treatment related characteristic anomalies induced by other components of AML-treatment such as Ara C or Thioguanin could be defined soon that so far cannot directly be related to certain drugs. Furthermore in a substantial proportion of pts. (34,65%) it cannot be excluded, that clonal evolution had been modulated by antecedent antileukemic chemotherapy. Preliminary data suggest that at least in t-AML following breast cancer treatment polymorphisms of GST influence the risk of t-AML.

Myeloid Malignancies Induced by Alkylating Agents in Nf1 Mice

Therapy-related acute myeloid leukemia and myelodysplastic syndrome (t-AML and MDS) are severe late complications of treatment with genotoxic chemotherapeutic agents. Children with neurofibromatosis type 1 (NF1) are predisposed to malignant myeloid disorders that are associated with inactivation of the NF1 tumor suppressor gene in the leukemic clone. Recent clinical data suggest that NF1 might be also associated with an increased risk of t-AML after treatment with alkyating agents. To test this hypothesis, we administered cyclophosphamide or etoposide to cohorts of wild-type and heterozygousNf1 knockout mice. Cyclophosphamide exposure cooperated strongly with heterozygous inactivation of Nf1 in myeloid leukemogenesis, while etoposide did not. Somatic loss of the normalNf1 allele correlated with clinical disease and was more common in 129/Sv mice than in 129/Sv × C57BL/6 animals. Leukemic cells showing loss of heterozygosity at Nf1 retained a structural allele on each chromosome 11 homolog. These studies establish a novel in vivo model of alkylator-induced myeloid malignancy that will facilitate mechanistic and translational studies.

Neuroblastoma and treatment-related myelodysplasia/leukemia: the Memorial Sloan-Kettering experience and a literature review.

To assess treatment-related myelodysplasia/leukemia (t-AML) in neuroblastoma patients by a review of the Memorial Sloan-Kettering Cancer Center (MSKCC) data and the literature. We studied 380 previously untreated and treated MSKCC patients. Low-risk patients received no cytotoxic therapy. High-risk patients received the N4, N5, or N6 regimens. Dosing per cycle and cumulative dosing of leukemogenic agents peaked with N6, which included four cycles of cyclophosphamide 4,200 mg/m2 and doxorubicin 75 mg/m2, plus three cycles of cisplatin 200 mg/m2 and etoposide 600 mg/m2. We reviewed the literature. t-AML occurred in six MSKCC patients, which included three of 53 patients in whom the only chemotherapy consisted of N6, and three patients treated for relapsed or refractory neuroblastoma; no case of leukemia emerged among the 50 low-risk patients. Four cases were found incidentally in routine follow-up bone marrow tests. The 36-month cumulative incidence of t-AML in the N6 cohort was 7% (95% confidence interval, 0 to 15). Published data parallel the MSKCC experience in that t-AML after neuroblastoma was once rare but has become less so since the mid-1980s, when the intensified use of topoisomerase-II inhibitors and alkylators first gained wide acceptance and produced better response rates and longer survival. Neuroblastoma itself is not associated with a host susceptibility to leukemia. However, current neuroblastoma treatment programs that use high-dose cyclophosphamide, cisplatin, and topoisomerase-II inhibitors may entail a considerable risk for t-AML. The incidence of t-AML in neuroblastoma patients may be underestimated because treatment and clinical factors can mask its presence. Efforts to devise effective but less leukemogenic treatment for neuroblastoma or to truncate leukemogenic therapy, eg, by exploiting molecular techniques for the early identification of complete remission, are warranted.

Therapy-related acute myeloid leukemia following treatment with epipodophyllotoxins: estimating the risks.

In the past decade, therapy-related acute myeloid leukemia (t-AML) following treatment with regimens that include inhibitors of topoisomerase-II (TOPO-II) has been reported with increasing frequency. These cases of t-AML generally have a shorter latency period than t-AML following alkylator therapy, are associated with chromosomal translocations (especially involving chromosome band 11q23), and usually present as M4 or M5 FAB subtype. Although the epipodophyllotoxins (etoposide and teniposide) have been most often implicated, similar cases of t-AML occur following therapy with other classes of Topo-II inhibitors (e.g., anthracyclines). There is wide variation in published studies in the estimates of risk of t-AML following epipodophyllotoxin therapy. These varying estimates may reflect a number of factors, including: small sample size leading to large confidence intervals around risk estimates; varying susceptibility of different patient populations; varying schedules of epipodophyllotoxin administration; different cumulative doses of epipodophyllotoxins; and administration of epopodophyllotoxins with additional agents that may alter the leukemogenic effect of the epipodophyllotoxins. Available data suggest that children with acute lymphocytic leukemia (ALL) treated with high cumulative doses of epipodophyllotoxins using either weekly or twice-weekly schedules of administration have a relatively high risk of developing t-AML (5-12% cumulative risk). On the other hand, germ cell patients treated with relatively low cumulative doses of etoposide (usually 1,500-2,500 mg/m2) appear to have a low risk for developing t-AML. There is inadequate experience at this time with higher cumulative doses of etoposide (e.g., 4,000-5,000 mg/m2 as used for pediatric solid tumors) given on a daily x 5 schedule to allow estimates of risk to be developed for this schedule and cumulative dose. The Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI) has developed a monitoring plan designed to obtain reliable estimates of the risk of t-AML following epipodophyllotoxin treatment. Twelve Cooperative Group clinical trials that use epipodophyllotoxins at either low (< 1,500 mg/m2), moderate (1,500-3,999 mg/m2), or higher cumulative doses (> 4,000 mg/m2) are being prospectively monitored for cases of t-AML occurring among patients entered onto the trials.