Leukemogenesis Induced by an Activating β-catenin mutation in Osteoblasts

Cells of the osteoblast lineage affect homing, 1, 2 number of long term repopulating hematopoietic stem cells (HSCs) 3, 4, HSC mobilization and lineage determination and B lymphopoiesis 5-8. More recently osteoblasts were implicated in pre-leukemic conditions in mice 9, 10. Yet, it has not been shown that a single genetic event taking place in osteoblasts can induce leukemogenesis. We show here that in mice, an activating mutation of β-catenin in osteoblasts alters the differentiation potential of myeloid and lymphoid progenitors leading to development of acute myeloid leukemia (AML) with common chromosomal aberrations and cell autonomous progression. Activated β- catenin stimulates expression of the Notch ligand Jagged-1 in osteoblasts. Subsequent activation of Notch signaling in HSC progenitors induces the malignant changes. Demonstrating the pathogenetic role of the Notch pathway, genetic or pharmacological inhibition of Notch signaling ameliorates AML. Nuclear accumulation and increased β-catenin signaling in osteoblasts was also identified in 38% of patients with MDS/AML. These patients showed increased Notch signaling in hematopoietic cells. These findings demonstrate that genetic alterations in osteoblasts can induce AML, identify molecular signals leading to this transformation and suggest a potential novel pharmacotherapeutic approach to AML

Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML

BACKGROUND: Patients with relapsed or refractory acute myeloid leukemia (AML) with mutations in the FMS-like tyrosine kinase 3 gene (FLT3) infrequently have a response to salvage chemotherapy. Gilteritinib is an oral, potent, selective FLT3 inhibitor with single-agent activity in relapsed or refractory FLT3-mutated AML. METHODS: In a phase 3 trial, we randomly assigned adults with relapsed or refractory FLT3-mutated AML in a 2:1 ratio to receive either gilteritinib (at a dose of 120 mg per day) or salvage chemotherapy. The two primary end points were overall survival and the percentage of patients who had complete remission with full or partial hematologic recovery. Secondary end points included event-free survival (freedom from treatment failure [i.e., relapse or lack of remission] or death) and the percentage of patients who had complete remission. RESULTS: Of 371 eligible patients, 247 were randomly assigned to the gilteritinib group and 124 to the salvage chemotherapy group. The median overall survival in the gilteritinib group was significantly longer than that in the chemotherapy group (9.3 months vs. 5.6 months; hazard ratio for death, 0.64; 95% confidence interval [CI], 0.49 to 0.83; P\u3c0.001). The median event-free survival was 2.8 months in the gilteritinib group and 0.7 months in the chemotherapy group (hazard ratio for treatment failure or death, 0.79; 95% CI, 0.58 to 1.09). The percentage of patients who had complete remission with full or partial hematologic recovery was 34.0% in the gilteritinib group and 15.3% in the chemotherapy group (risk difference, 18.6 percentage points; 95% CI, 9.8 to 27.4); the percentages with complete remission were 21.1% and 10.5%, respectively (risk difference, 10.6 percentage points; 95% CI, 2.8 to 18.4). In an analysis that was adjusted for therapy duration, adverse events of grade 3 or higher and serious adverse events occurred less frequently in the gilteritinib group than in the chemotherapy group; the most common adverse events of grade 3 or higher in the gilteritinib group were febrile neutropenia (45.9%), anemia (40.7%), and thrombocytopenia (22.8%). CONCLUSIONS: Gilteritinib resulted in significantly longer survival and higher percentages of patients with remission than salvage chemotherapy among patients with relapsed or refractory FLT3-mutated AML. (Funded by Astellas Pharma; ADMIRAL ClinicalTrials.gov number, NCT02421939.)

Invasion and Replication of Brucella Abortus in Three Different Trophoblastic Cell Lines

This study was performed to compare the replication of the pathogenic strain Brucella abortus 2308 in three trophoblastic cell lines derived bovine placentas at different gestational stages. The trophoblastic cell lines were obtained from a 13–15 day embryo, from 5‐month placentomal tissue and from an 8‐month extra‐placentomal portion of the placenta. The infection rate was similar in all cell lines at 4 h. Colony‐forming Units were counted at 4, 8, 12, 24 and 30 h post‐inoculation. At 12, 16, 24 and 30 h B. abortus rapidly replicated within the 5‐month and 8‐month trophoblastic cell lines, but grew slowly within trophoblastic cells derived from embryonic tissue. Electron microscopic studies consistently showed clusters of B. abortus in trophoblastic cells derived from 5‐ and 8‐month placentas, while few cells of the embryonic line were infected and these contained only 1–2 bacteria per cell. It was concluded that B. abortus can infect trophoblastic cells throughout the gestational period but bacterial multiplication does not occur in these cells before middle or late gestation. © 1994 Blackwell Verlag Gmb

A cause-specific hazard rate analysis of prognostic factors among 199 adults with acute lymphoblastic leukemia: the Memorial Hospital experience since 1969

Results of a multivariable analysis of prognostic factors are reported for 199 previously untreated adults with acute lymphoblastic leukemia (ALL). These patients have long-term follow-up, and the probability of cure is estimated at approximately 35%. The cause-specific hazard rate analysis found lower rates of achieving complete remission (CR) in patients with WBC greater than 10,000/microL, AUL (undifferentiated) morphology, and older age. Since these patients required additional time to respond, fewer of them actually achieved CR. Characteristics directly associated with a higher rate of death during induction therapy due to severe bone marrow suppression were low serum albumin concentration (less than or equal to 3.5 g/dL), age greater than 50 years, acute undifferentiated leukemia (AUL) morphology, low Karnofsky performance status, and weight loss greater than 5%. Factors associated with a higher rate of relapse were WBC greater than 20,000/microL, non-T cell ALL, age greater than 60 years, Ph' + ALL, and time to achieve CR greater than 5 weeks. These criteria were used to identify patients at high risk of relapse. In addition, the predictive value of high WBC was found to disappear by 18 months of continuous CR. Finally, the rate of death following first relapse was higher in patients with a short first remission duration, high percentage weight loss at initial diagnosis, and older age. In summary, factors associated with a higher rate of death during attempted induction (ie, low albumin, high percent weight loss, and poor performance status) had no association with the patient's ability to remain relapse-free. Conversely, factors correlating with more extensive or resistant disease (ie, high WBC, null or B cell ALL, or Ph' + ALL) showed no association with the ability to tolerate therapy. Thus, a less toxic but more effective induction regimen is needed for patients with a poor clinical status, whereas a more intensive form of therapy appears warranted for patients presenting with more extensive or resistant disease