The cellular targets of primary mutations and malignant transformation remain elusive in most cancers. Here, we show that clinically and genetically different subtypes of acute lymphoblastic leukemia (ALL) originate and transform at distinct stages of hematopoietic development. Primary ETV6-RUNX1 (also known as TEL-AML1) fusions and subsequent leukemic transformations were targeted to committed B-cell progenitors. Major breakpoint BCR-ABL1 fusions (encoding P210 BCR-ABL1) originated in hematopoietic stem cells (HSCs), whereas minor BCR-ABL1 fusions (encoding P190 BCR-ABL1) had a B-cell progenitor origin, suggesting that P190 and P210 BCR-ABL1 ALLs represent largely distinct tumor biological and clinical entities. The transformed leukemia-initiating stem cells in both P190 and P210 BCR-ABL1 ALLs had, as in ETV6-RUNX1 ALLs, a committed B progenitor phenotype. In all patients, normal and leukemic repopulating stem cells could successfully be separated prospectively, and notably, the size of the normal HSC compartment in ETV6-RUNX1 and P190 BCR-ABL1 ALLs was found to be unaffected by the expansive leukemic stem cell population.

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, and until recently prophylactic cranial radiotherapy (CRT) was important for achieving longterm survival. Hypothalamic-pituitary hormone insufficiency is a well-recognized consequence of CRT for childhood cancer. Another problem is increased cardiovascular risk, which has been shown in long-term survivors of other childhood cancers. In the only previously reported study on cardiovascular risk after childhood ALL, obesity and dyslipidemia were recorded in a small subgroup treated with CRT, compared with patients treated with chemotherapy. The mechanisms behind the increase in cardiovascular risk in survivors of childhood cancer are not clarified.The aim of the present study was to elucidate mechanisms of increased cardiovascular risk in former childhood ALL patients. A group of 44 ALL survivors (23 males, median age 25 yr, range 19 -32 yr at the time of study) treated with CRT (median 24 Gy, 18 -30 Gy) at a median age of 5 yr (1-18 yr) and chemotherapy were investigated for prevalence of GH deficiency and cardiovascular risk factors. Comparison was made with controls randomly selected from the general population and individually matched for sex, age, smoking habits, and residence. All patients and controls underwent a GHRHarginine test, and patients with a peak GH 3.9 g/liter or greater were further investigated with an additional insulin tolerance test.Significantly higher plasma levels of insulin (P ‫؍‬ 0.002), blood glucose (P ‫؍‬ 0.01), and serum levels of low-density lipoprotein cholesterol, apolipoprotein (Apo) B, triglycerides, fibrinogen, and leptin (all P < 0.05) were recorded among the ALL patients, compared with controls. Furthermore, the serum levels of high-density lipoprotein cholesterol (P ‫؍‬ 0.03) and Apo A1 (P ‫؍‬ 0.005) were significantly lower among the patients. Compared with controls, the patients had higher body mass index and waist to hip ratio, and body composition measured with dual-energy x-ray absorptiometry showed significantly higher fat mass and lower lean mass (P < 0.001). Forty of 44 ALL patients (91%) were considered GH deficient according to the insulin tolerance test and/or the GHRHarginine test, and the rest were considered GH insufficient.In patients, peak GH during GHRH-arginine was significantly negatively correlated to total body fat mass measured with dual-energy x-ray absorptiometry (r ‫؍‬ ؊0.48, P ‫؍‬ 0.001), waist to hip ratio (r ‫؍‬ ؊0.32, P ‫؍‬ 0.03), plasma insulin (r ‫؍‬ ؊0.49, P ‫؍‬ 0.001), and leptin (r ‫؍‬ ؊0.46, P ‫؍‬ 0.002). Moreover, a significantly positive correlation was recorded with highdensity lipoprotein cholesterol (r ‫؍‬ 0.38, P ‫؍‬ 0.012). Using Doppler echocardiography, a marked reduction in cardiac dimensions and performance (ejection fraction P < 0.001 and fractional shortening P ‫؍‬ 0.01), compared with controls, was recorded.In conclusion, at a median 17 yr after treatment with CRT and chemotherapy in former childhood ALL patients, a significant increase in cardiovascul...

PURPOSE: To assess the risk of death in patients who survive more than 5 years after diagnosis of childhood cancer and to evaluate causes of death in fatal cases. PATIENTS AND METHODS: This was a population-based study in the five Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden) using data of the nationwide cancer registries and the cause-of-death registries. The study cohort included 13,711 patients who were diagnosed with cancer before the age of 20 years between 1960 and 1989 and who survived at least 5 years from diagnosis. By December 31, 1995, 1,422 patients had died, and death certificates were assessed in 1,402. Standardized mortality ratios (SMRs) for validated causes of death were calculated based on 156,046 patient-years at risk. RESULTS: The overall SMR was 10.8 (95% confidence interval [CI], 10.3 to 11.5), mainly due to high excess mortality from the primary cancer. SMR for second cancer was 4.9 (95% CI, 3.9 to 5.9) and was 3.1 (95% CI, 2.8 to 3.5) for noncancer death. The pattern of causes of death varied markedly between different groups of primary cancer diagnoses and was highly dependent on time passed since diagnosis. Overall late mortality was significantly lower in patients treated during the most recent period of time, 1980 to 1989, compared with those treated from 1960 to 1979 (hazard ratio, 0.61; 95% CI, 0.54 to 0.70), and there was no increase in rates of death due to cancer treatment. CONCLUSION: Long-term survivors of childhood cancer had an increased mortality rate, mainly dying from primary cancers. However, modern treatments have reduced late cancer mortality without increasing the rate of therapy-related deaths.