We report gene expression and other analyses to elucidate the molecular characteristics of acute lymphoblastic leukemia (ALL) in children with Down syndrome (DS). We find that by gene expression DS-ALL is a highly heterogeneous disease not definable as a unique entity. Nevertheless, 62% (33/53) of the DS-ALL samples analyzed were characterized by high expression of the type I cytokine receptor CRLF2 caused by either immunoglobulin heavy locus (IgH@) translocations or by interstitial deletions creating chimeric transcripts P2RY8-CRLF2. In 3 of these 33 patients, a novel activating somatic mutation, F232C in CRLF2, was identified. Consistent with our previous research, mutations in R683 of JAK2 were identified in 10 specimens (19% of the patients) and, interestingly, all 10 had high CRLF2 expression. Cytokine receptor-like factor 2 (CRLF2) and mutated Janus kinase 2 (Jak2) cooperated in conferring cytokine-independent growth to BaF3 pro-B cells. Intriguingly, the gene expression signature of DS-ALL is enriched with DNA damage and BCL6 responsive genes, suggesting the possibility of B-cell lymphocytic genomic instability. Thus, DS confers increased risk for genetically highly diverse ALLs with frequent overexpression of CRLF2, associated with activating mutations in the receptor itself or in JAK2. Our data also suggest that the majority of DS children with ALL may benefit from therapy blocking the CRLF2/JAK2 pathways. (Blood.
Pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has achieved an 80% cure rate as a result of a risk-adapted therapy largely based on minimal residual disease (MRD) monitoring. However, relapse is still the most frequent adverse event, occurring mainly in the patients with intermediate MRD levels (intermediate risk, IR), emphasizing the need for new prognostic markers. We analyzed the prognostic impact of cytokine receptor-like factor 2 (CRLF2) over-expression and P2RY8-CRLF2 fusion in 464 BCP-ALL patients (not affected by Down syndrome and BCR-ABL negative) enrolled in the AIEOP-BFM ALL2000 study in Italy. In 22/464 (4.7%) samples, RQ-PCR showed CRLF2 over-expression (X20 times higher than the overall median). P2RY8-CRLF2 fusion was detected in 22/365 (6%) cases, with 10/22 cases also showing CRLF2 over-expression. P2RY8-CRLF2 fusion was the most relevant prognostic factor independent of CRLF2 over-expression with a threefold increase in risk of relapse. Significantly, the cumulative incidence of relapse of the P2RY8-CRLF2 þ patients in the IR group was high (61.1% ± 12.9 vs 17.6% ± 2.6, Po0.0001), similar to high-risk patients in AIEOP-BFM ALL2000 study. These results were confirmed in a cohort of patients treated in Germany. In conclusion, P2RY8-CRLF2 identifies a subset of BCP-ALL patients currently stratified as IR that could be considered for treatment intensification.
We investigated the engraftment properties and impact on patient outcome of 50 pediatric acute lymphoblastic leukemia (ALL) samples transplanted into NOD/SCID mice. Time to leukemia (TTL) was determined for each patient sample engrafted as weeks from transplant to overt leukemia. Short TTL was strongly associated with high risk for early relapse, identifying an independent prognostic factor. This high-risk phenotype is reflected by a gene signature that upon validation in an independent patient cohort (n = 197) identified a high-risk cluster of patients with early relapse. Furthermore, the signature points to independent pathways, including mTOR, involved in cell growth and apoptosis. The pathways identified can directly be targeted, thereby offering additional treatment approaches for these high-risk patients.
Purpose: In chronic lymphocytic leukemia (CLL), TP53 mutations are associated with reduced survival and resistance to standard chemoimmunotherapy (CIT). Nevertheless, the clinical impact of subclonal TP53 mutations below 10% to 15% variant allele frequency (VAF) remains unclear. Experimental Design: Using a training/validation approach, we retrospectively analyzed the clinical and biological features of TP53 mutations above (high-VAF) or below (low-VAF) the previously reported 10.0% VAF threshold, as determined by deep next-generation sequencing. Clinical impact of low-VAF TP53 mutations was also confirmed in a cohort (n = 251) of CLL treated with fludarabine-cyclophosphamide-rituximab (FCR) or FCR-like regimens from two UK trials. Results: In the training cohort, 97 of 684 patients bore 152 TP53 mutations, while in the validation cohort, 71 of 536 patients had 109 TP53 mutations. In both cohorts, patients with the TP53 mutation experienced significantly shorter overall survival (OS) than TP53 wild-type patients, regardless of the TP53 mutation VAF. By combining TP53 mutation and 17p13.1 deletion (del17p) data in the total cohort (n = 1,220), 113 cases were TP53 mutated only (73/113 with low-VAF mutations), 55 del17p/TP53 mutated (3/55 with low-VAF mutations), 20 del17p only, and 1,032 (84.6%) TP53 wild-type. A model including low-VAF cases outperformed the canonical model, which considered only high-VAF cases (c-indices 0.643 vs. 0.603, P < 0.0001), and improved the prognostic risk stratification of CLL International Prognostic Index. Clinical results were confirmed in CIT-treated cases (n = 552) from the retrospective cohort, and the UK trials cohort. Conclusions: TP53 mutations affected OS regardless of VAF. This finding can be used to update the definition of TP53 mutated CLL for clinical purposes.
Key Points miR-486-5p, a GATA1 regulated miR, is expressed in ML-DS and enhances their aberrant erythroid phenotype. miR-486-5p cooperates with GATA1s to promote the survival of pre-leukemic and leukemic cells.
functional annotation was done by gene set enrichment analysis (GSEA). Results: Genes downregulated after ETS1 silencing by siRNAs in 5 ABC DLBCL cell lines (TMD8, HBL-1, U2932, OCI-Ly10, SU-DHL-2) belonged to the signaling of BCR (NES 2.45 FDR <0.001), CD40 (NES 2.67 FDR <0.001), and NFKB/TNFA (NES 2.03 FDR 0.01), as well as to inflammatory response (NES 2.14 FDR 0.005) and differentiation (NES 2.5 FDR <0.001). Three candidate genes were selected for further studies according to the following educated guess criteria: i) potential biologic role; and ii) presence of binding sites for ETS factors in their promoter regions. HCST, RGS1 and FAIM3 were confirmed to be downregulated, by qPCR, also after silencing with shRNA. Their expression in clinical specimens was confirmed in two large series of 181 and 233 DLBCL cases, respectively. FAIM3 expression was higher in ABC DLBCL cases than germinal center type (GCB) DLBCL in both series (P < 0.0001), and a similar pattern was confirmed at protein level in cell lines derived from ABC (n = 6) or GCB DLBCL (n = 8). Conclusions: ETS1 positively regulates the expression of fundamental pathways in ABC DLBCL cells, including the BCR signaling. FAIM3, which codes for a high affinity IgM FC receptor overexpressed in chronic lymphocytic leukemia, appeared as a novel potential ETS1 transcription target, differentially regulated between ABC and GCB DLBCL, and requires additional investigation. Introduction: Stabilizing mutations of NOTCH1 occur in about 10% of chronic lymphocytic leukemia (CLL) cases at diagnosis, with a higher frequency in unmutated IGHV (IGHV-UM), immuno-chemorefractory or advanced disease phase CLL, and have been associated with particularly unfavourable prognosis (Rossi et al., Blood, 2012; Del Poeta et al., Br J Haematol, 2013; Stilgenbauer et al., Blood, 2014). In CLL, NOTCH1mutations cause accumulation of the active NOTCH1 iso-form, resulting in a sustained pathway activation. We therefore aimed at identifying molecular/biological features of NOTCH1 mutated (NOTCH1-mut) CLL. Methods: NOTCH1 mutations were investigated by NGS. Gene expression profile (GEP) was performed on a one-color 4x44K platform. Validations were performed by QRT-PCR, western blotting, flow cytometry. Cell proliferation was evaluated by CellTrace assay. Results: i) A GEP comparing 10 IGHV-UM CLL cases (5 NOTCH1-mut; 15%-37% of NOTCH1-mut alleles) selected nucleophosmin-1 (NPM1) and genes codifying for ribosomal proteins (RNPs) as up-regulated in NOTCH1-mut cases. Results were validated in an independent series of 188 cases (76 NOTCH1-mut). ii) Western blotting in 11 CLL cases (5 NOTCH1-mut) confirmed a higher NPM1 protein expression in NOTCH1-mut cases,with a direct correlation with NOTCH1 expression (r = 0.814). In NOTCH1-mut cases, the NPM1 high subpopulation, isolated by cell sorting, showed higher mutational load than the NPM1 low subpopulation. Iii) EDTA treatment of 12 CLL cases (6 NOTCH1-mut), activated NOTCH1 signaling, as by HES1 and DTX1 induction, and up-regulated NPM1 and othe...
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.
SummaryThe prognostic relevance of CRLF2-rearrangements in childhood acute B-cell precursor lymphoblastic leukaemia (ALL), was assessed by a comparative analysis of 114 non-Down-syndrome patients (99 P2RY8-CRLF2+, 15 IGH@-CRLF2+), 76 from the AIEOP-BFM ALL 2000 and 38 from the MRC ALL97 trials. The 6-year cumulative relapse incidence of P2RY8-CRLF2+ patients treated on the two trials was not statistically different: 0Á37 ± 0Á06 vs. 0Á25 ± 0Á08 (P = 0Á194). In contrast, 0/9 IGH@-CRLF2+ AIEOP-BFM, but 5/6 ALL97 patients relapsed. Conclusively, P2RY8-CRLF2+ patients had an intermediate protocol-independent outcome while the different prognosis of IGH@-CRLF2+ patients could be related to the different structures of the applied treatment protocols.
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