Prognostic Role of Minimal Disseminated Disease and NOTCH1/FBXW7 Mutational Status in Children with Lymphoblastic Lymphoma: The AIEOP Experience.

NOTCH1/FBXW7 (N/F) mutational status at diagnosis is employed for T-cell lymphoblastic lymphoma (T-LBL) patients' stratification in the international protocol LBL 2018. Our aim was to validate the prognostic role of Minimal Disseminated Disease (MDD) alone and in combination with N/F mutational status in a large retrospective series of LBL pediatric patients. MDD was analyzed in 132 bone marrow and/or peripheral blood samples by flow cytometry. Mutations in N/F genes were analyzed on 58 T-LBL tumor biopsies. Using the previously established cut-off of 3%, the four-year progression-free survival (PFS) was 57% for stage I-III patients with MDD ≥ 3% versus 80% for patients with MDD inferior to cut-off (p = 0.068). We found a significant worsening in the four-year PFS for nonmutated (51 ± 12%) compared to mutated patients (100%, p = 0.0013). Combining MDD and N/F mutational status in a subgroup of available cases, we found a statistically significant difference in the four-year PFS for different risk groups (p = 0.0012). Overall, our results demonstrate that N/F mutational status has a more relevant prognostic value than MDD at diagnosis. However, the combination of N/F mutations with MDD analysis could identify patients with very aggressive disease, which might benefit from a more intensive treatment.

Targeting the plasticity of mesenchymal stromal cells to reroute the course of acute myeloid leukemia.

Bone marrow (BM) microenvironment contributes to the regulation of normal hematopoiesis through a finely tuned balance of self-renewal and differentiation processes, cell-cell interaction, and secretion of cytokines that during leukemogenesis are altered and favor tumor cell growth. In pediatric acute myeloid leukemia (AML), chemotherapy is the standard of care, but >30% of patients still relapse. The need to accelerate the evaluation of innovative medicines prompted us to investigate the role of mesenchymal stromal cells (MSCs) in the leukemic niche to define its contribution to the mechanism of leukemia drug escape. We generated a humanized 3-dimensional (3D) niche with AML cells and MSCs derived from either patients (AML-MSCs) or healthy donors. We observed that AML cells establish physical connections with MSCs, mediating a reprogrammed transcriptome inducing aberrant cell proliferation and differentiation and severely compromising their immunomodulatory capability. We confirmed that AML cells modulate h-MSCs transcriptional profile promoting functions similar to the AML-MSCs when cocultured in vitro, thus facilitating leukemia progression. Conversely, MSCs derived from BM of patients at time of disease remission showed recovered healthy features at transcriptional and functional levels, including the secretome. We proved that AML blasts alter MSCs activities in the BM niche, favoring disease development and progression. We discovered that a novel AML-MSC selective CaV1.2 channel blocker drug, lercanidipine, is able to impair leukemia progression in 3D both in vitro and when implanted in vivo if used in combination with chemotherapy, supporting the hypothesis that synergistic effects can be obtained by dual targeting approaches.

High expression of miR-125b-2 and SNORD116 noncoding RNA clusters characterize ERG-related B cell precursor acute lymphoblastic leukemia.

ERG-related leukemia is a B cell precursor acute lymphoblastic leukemia (BCP ALL) subtype characterized by aberrant expression of DUX4 and ERG transcription factors, and highly recurrent ERG intragenic deletions. ERG-related patients have remarkably favorable outcome despite a high incidence of inauspicious IKZF1 aberrations.We describe clinical and genomic features of the ERG-related cases in an unselected cohort of B-other BCP ALL pediatric patients enrolled in the AIEOP ALL 2000 therapeutic protocol. We report a small noncoding RNA signature specific of ERG-related group, with up-regulation of miR-125b-2 cluster on chromosome 21 and several snoRNAs in the Prader-Willi locus at 15q11.2, including the orphan SNORD116 cluster.

Expression of the immunoglobulin superfamily cell membrane adhesion molecule Cd146 in acute leukemia.

BACKGROUND: The expression of the immunoglobulin superfamily cell membrane adhesion molecule CD146 has been reported on several normal and pathological cell types in human. The aim of this study was to investigate CD146 expression in acute leukemia using a multiparametric cytofluorimetric approach. METHODS: Cytofluorimetric and cytogenetic studies were performed on peripheral blood and bone marrow samples from 162 patients with acute myeloid leukemia (AML, n = 121) and acute lymphoblastic leukemia (ALL, n = 41). ALL patients were subdivided in B-ALL (n = 38) and T-ALL (n = 3). Adult (n = 18) and pediatric (n = 20) B-ALL were considered as a whole group. RESULTS: Four out of 121 (3.3%) AML cases, 14/38 (36.8%) B-ALL, and 2/3 (66.6%) T-ALL expressed CD146 on 12-98% of blasts (p < 0.001). CD146 expression was not observed in 10 healthy controls. Among B-ALL CD146-positive cases, 78.6% were associated with a "common"/BII-ALL and 21.4% with a pre-B/BIII-ALL immunophenotype while pro-B/BI-ALL and mature-B/BIV-ALL cases were CD146-negative. Statistical analysis showed CD146 expression strongly associated with Ph+ positivity in B-ALL with the highest percentage of CD146-positive blasts in all Ph-positive B-ALL cases (84 ± 22% Ph-positive B-ALL SD vs. 40 ± 24% SD in Ph-negative B-ALL; p < 0,001). CONCLUSION: In our series, CD146 was expressed in all cases of Ph-positive B-ALL and in the vast majority of T-ALL, whereas it was rarely expressed by AML blasts. We suggest that CD146 may be considered as an additional marker for acute lymphoblastic leukemia diagnosis and monitoring of minimal residual disease in those cases which are CD146-positive at diagnosis. © 2015 International Clinical Cytometry Society.

Effects of exposure to extremely low frequency electro-magnetic fields on circadian rhythms and distribution of some leukocyte differentiation antigens in dairy cows.

OBJECTIVE: To investigate the effects of extremely low frequency magnetic and electric fields (ELFEMFs) emitted from 380 kV transmission lines on some leukocyte differentiation antigens in dairy cows. METHODS: The study was carried out in 5 cows exposed to 1.98-3.28 microT of ELFEMFs and in 5 control cows exposed to 0.2-0.7 microT of ELFEMFs. Following haematological and immunologic parameters were measured in both groups: WBC, CD45R, CD6, CD4, CD8, CD21, and CD11B leukocyte antigen expression. RESULTS: Some of the haematological and immunologic parameters under investigation were similar in both groups. However, CD8 (T lymphocyte surface antigen) was higher in the exposed group (1.35 +/- 0.120 vs. 0.50 +/- 0.14 x 10(3)/mL). Furthermore, the CD4/CD8 ratio (0.84 +/- 0.05 and 2.19 +/- 0.16 for exposed and not exposed cows respectively) and circadian rhythm were different between the two groups. CONCLUSION: Exposure to ELFEMFs is responsible of the abnormal temporal variations and distribution of some haematological and immunological parameters in dairy cows.