Endogenous expression of HrasG12V induces developmental defects and neoplasms with copy number imbalances of the oncogene

We developed mice with germline endogenous expression of oncogenic Hras to study effects on development and mechanisms of tumor initiation. They had high perinatal mortality, abnormal cranial dimensions, defective dental ameloblasts, and nasal septal deviation, consistent with some of the features of human Costello syndrome. These mice developed papillomas and angiosarcomas, which were associated with HrasG12V allelic imbalance and augmented Hras signaling. Endogenous expression of HrasG12V was also associated with a higher mutation rate in vivo. Tumor initiation by HrasG12V likely requires augmentation of signal output, which in papillomas and angiosarcomas is achieved via increased Hras-gene copy number, which may be favored by a higher mutation frequency in cells expressing the oncoprotein

Marrow versus peripheral blood for geno-identical allogeneic stem cell transplantation in acute myelocytic leukemia: Influence of dose and stem cell source shows better outcome with rich marrow

Several studies have compared bone marrow (BM) and peripheral blood (PB) as stem cell sources in patients receiving allografts, but the cell doses infused have not been considered, especially for BM. Using the ALWP/EBMT registry, we retrospectively studied 881 adult patients with acute myelocytic leukemia (AML), who received a non-T-depleted allogeneic BM (n = 515) or mobilized PB (n = 366) standard transplant, in first remission (CR1), from an HLA-identical sibling, over a 5-year period from January 1994. The BM cell dose ranged from 0.17 to 29 × 108/kg with a median of 2.7 × 108/kg. The PB cell dose ranged from 0.02 to 77 × 10 8/kg with a median of 9.3 × 108/kg. The median dose for patients receiving BM (2.7 × 108/kg) gave the greatest discrimination. In multivariate analyses, high-dose BM compared to PB was associated with lower transplant-related mortality (RR = 0.61; 95% CI, 0.39-0.98; P = .04), better leukemia-free survival (RR = 0.65; 95% CI, 0.46-0.91; P = .013), and better overall survival (RR = 0.64; 95% CI, 0.44-0. 92; P = .016). The present study in patients with AML receiving allografts in first remission indicates a better outcome with BM as compared to PB, when the dose of BM infused is rich. © 2003 by The American Society of Hematology

Marrow versus peripheral blood for geno-identical allogeneic stem cell transplantation in acute myelocytic leukemia: Influence of dose and stem cell source shows better outcome with rich marrow

PubMed ID: 12829583Several studies have compared bone marrow (BM) and peripheral blood (PB) as stem cell sources in patients receiving allografts, but the cell doses infused have not been considered, especially for BM. Using the ALWP/EBMT registry, we retrospectively studied 881 adult patients with acute myelocytic leukemia (AML), who received a non-T-depleted allogeneic BM (n = 515) or mobilized PB (n = 366) standard transplant, in first remission (CR1), from an HLA-identical sibling, over a 5-year period from January 1994. The BM cell dose ranged from 0.17 to 29 × 10 8 /kg with a median of 2.7 × 10 8 /kg. The PB cell dose ranged from 0.02 to 77 × 10 8 /kg with a median of 9.3 × 10 8 /kg. The median dose for patients receiving BM (2.7 × 10 8 /kg) gave the greatest discrimination. In multivariate analyses, high-dose BM compared to PB was associated with lower transplant-related mortality (RR = 0.61; 95% CI, 0.39-0.98; P = .04), better leukemia-free survival (RR = 0.65; 95% CI, 0.46-0.91; P = .013), and better overall survival (RR = 0.64; 95% CI, 0.44-0. 92; P = .016). The present study in patients with AML receiving allografts in first remission indicates a better outcome with BM as compared to PB, when the dose of BM infused is rich. © 2003 by The American Society of Hematology