Molecular alterations of the IDH1 gene in AML: a Children's Oncology Group and Southwest Oncology Group study.

Recent whole-genome sequencing efforts led to the identification of IDH1(R132) mutations in acute myeloid leukemia (AML) patients. We studied the prevalence and clinical implications of IDH1 genomic alterations in pediatric and adult AML. Diagnostic DNA from 531 AML patients treated on Children's Oncology Group trial COG-AAML03P1 (N=257), and Southwest Oncology Group trials SWOG-9031, SWOG-9333 and SWOG-9500 (N=274), were tested for IDH1 mutations. Codon R132 mutations were absent in the pediatric cohort, but were found in 12 of 274 adult patients (4.4%, 95% CI 2.3-7.5). IDH1(R132) mutations occurred most commonly in patients with normal karyotype, and those with FLT3/ITD and NPMc mutations. Patients with IDH1(R132) mutations trended toward higher median diagnostic white blood cell counts (59.2 x 10(9) vs 29.1 x 10(9) per liter, P=0.19) than those without mutations, but the two groups did not differ significantly in age, bone marrow blast percentage, overall survival or relapse-free survival. Eleven patients (2.1%) harbored a novel V71I sequence alteration, which was found to be a germ-line polymorphism. IDH1 mutations were not detected in pediatric AML, and are uncommon in adult AML.

Leukemia in donor cells after allogeneic hematopoietic stem cell transplant.

The development of leukemia in donor cells after allogeneic hematopoietic stem cell transplant is an extremely rare event. We report here the case of a patient who developed myelodysplastic syndrome/acute myeloid leukemia, in cells of donor origin 3.5 years after related donor HSCT for refractory chronic lymphocytic leukemia and therapy-induced myelodysplastic syndrome. The origin of the leukemia was determined by analysis of minisatillite polymorphism tested on CD34(+) cells.

Non-leukemic autologous reconstitution after allogeneic bone marrow transplantation for Ph-positive chronic myelogenous leukemia: extended remission preceding eventual relapse.

Autologous reconstitution is the recovery of autologous hematopoietic function after failure of an allogeneic graft to establish sustained hematopoiesis either with or without preceding donor engraftment. We reviewed 9 years experience of the University of Minnesota and identified 10 of 291 patients who underwent allogeneic BMT for Ph-positive CML and developed non-leukemic autologous reconstitution. All patients received the same preparative regimen with cyclophosphamide and total body irradiation. Eight patients had a 6/6-antigen matched donor. Eight patients received their graft from an unrelated donor. In five cases the graft was T cell-depleted. Non-malignant autologous reconstitution initially manifested as mixed chimerism in nine of 10 patients and lasted for a median of 11 (3-41) months. Eight patients have relapsed and four are still alive. The two relapse-free patients have died 24 and 48 months post transplant. Of the four surviving patients, two are in interferon-induced cytogenetic remission at 53+ and 101+ months of follow-up. Autologous non-leukemic reconstitution is uncommon, but appears to be a distinct clinical syndrome, perhaps occurring more frequently after unrelated donor BMT. Although usually followed by relapse, relapse-free survival may be prolonged.

Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia.

Long-range, directed migration is particularly dramatic in the cerebral cortex, where postmitotic neurons generated deep in the brain migrate to form layers with distinct form and function. In the X-linked dominant human disorder periventricular heterotopia (PH), many neurons fail to migrate and persist as nodules lining the ventricular surface. Females with PH present with epilepsy and other signs, including patent ductus arteriosus and coagulopathy, while hemizygous males die embryonically. We have identified the PH gene as filamin 1 (FLN1), which encodes an actin-cross-linking phosphoprotein that transduces ligand-receptor binding into actin reorganization, and which is required for locomotion of many cell types. FLN1 shows previously unrecognized, high-level expression in the developing cortex, is required for neuronal migration to the cortex, and is essential for embryogenesis.

Identification of a duplication of Xq28 associated with bilateral periventricular nodular heterotopia.

Bilateral periventricular nodular heterotopia (BPNH) is a malformation of neuronal migration and is characterized by nodules of heterotopic gray matter lining the lateral ventricles of the brain. The majority of BPNH patients are female and have epilepsy as a sole clinical manifestation of their disease. Familial BPNH has been mapped to Xq28 by linkage analysis. A multiple congenital anomaly-mental retardation syndrome (BPNH/MR) was recently delineated in three unrelated boys with BPNH, cerebellar hypoplasia, severe mental retardation, epilepsy, and syndactyly. High-resolution chromosome analysis revealed a subtle abnormality of Xq28 in one of the boys with BPNH/MR syndrome. FISH with cosmids and YACs from Xq28 further characterized this abnormality as a 2.25-3.25-Mb inverted duplication. No abnormality of Xq28 was detected by G-banding or FISH in the other two boys. These data support the linkage assignment of BPNH to band Xq28 and narrow the critical region to the distal 2.25-3.25 Mb of Xq28.

Genetic and environmental influences on baseline SCE.

Previous population-based studies have identified subject characteristics that, when combined, can account for approximately 20% of the observed interindividual variation in baseline SCE rates. In the present investigation, a classic twin study design was used to address the issue of the relevance of genetic factors to baseline SCE rates and to identify other demographic, hematologic, and exposure variables predictive of SCE rate. Questionnaire data and peripheral blood samples from 136 monozygotic and 88 dizygotic twins (age range: 25-81 years) were obtained. Among the large number of variables examined, univariate analyses (including ANOVA tests for the categorical variables and Pearson-product moment correlations for the quantitative variables) revealed smoking status, coffee drinking status, sex, white blood cell count, and absolute numbers of lymphocytes and neutrophils to have significant effects on SCE rates. A stepwise multiple regression analysis showed that together, smoking and coffee drinking status entered at the first step accounted for 21% of the observed variance in SCE, with a further 6% being contributed by the demographic and hematologic variables added in subsequent steps. Finally, the twin analyses showed that after adjustment of the data set for smoking and other significant predictors, genetic factors accounted for approximately 30% of the variation in SCE rates. Thus these data support the hypothesis of a significant genetic influence on baseline SCE.

Cytogenetic differentiation of Fanconi anemia, "idiopathic" aplastic anemia, and Fanconi anemia heterozygotes.

We have analyzed chromosome breaks in 8 patients with Fanconi anemia (FA), 42 with "idiopathic" aplastic anema (AA), 15 first-degree relatives of FA patients, and 13 controls. Their lymphocytes were treated in culture with three concentrations of mitomycin-C (MMC). A 60-fold increase in breaks was observed in FA patients as compared to AA patients, regardless of severity of clinical signs. The MMC-stress test was standardized to clearly differentiate FA from other pancytopenias in doubtful cases. Also, the effect of storage of MMC in solution was investigated. The data on SCEs of 12 subjects tested, 10 mo apart, showed an inverse relationship between length of storage of MMC and chromosome damage. The 10-month-old solution induced only one half as many SCEs as it induced at 4 months. Further, the usefulness and power of diepoxybutane (DEB) in detection of FA heterozygotes was investigated in 12 first-degree relatives of patients with Fanconi anemia and 12 healthy controls. The mean number of chromosome breaks per mitosis by DEB stress in obligate heterozygotes was 0.08 in comparison to 0.06 in controls. Four of twelve control subjects showed proportions of breaks almost identical to or higher than those of FA heterozygotes, ie, 0.12, 0.10, 0.10, and 0.11 breaks per mitosis. The responses of healthy controls to DEB could be separated into two groups: one with mean chromosome breaks of 0.11 per mitosis, and a second with mean breaks of 0.04 per mitosis. Thus, it appears that heterozygote detection by DEB stress of cultured lymphocytes is not unequivocal.