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Group 2 innate lymphoid cells (ILC2s) are involved in human diseases, such as allergy, atopic dermatitis and nasal polyposis, but their function in human cancer remains unclear. Here we show that, in acute promyelocytic leukaemia (APL), ILC2s are increased and hyper-activated through the interaction of CRTH2 and NKp30 with elevated tumour-derived PGD2 and B7H6, respectively. ILC2s, in turn, activate monocytic myeloid-derived suppressor cells (M-MDSCs) via IL-13 secretion. Upon treating APL with all-trans retinoic acid and achieving complete remission, the levels of PGD2, NKp30, ILC2s, IL-13 and M-MDSCs are restored. Similarly, disruption of this tumour immunosuppressive axis by specifically blocking PGD2, IL-13 and NKp30 partially restores ILC2 and M-MDSC levels and results in increased survival. Thus, using APL as a model, we uncover a tolerogenic pathway that may represent a relevant immunosuppressive, therapeutic targetable, mechanism operating in various human tumour types, as supported by our observations in prostate cancer. Group 2 innate lymphoid cells (ILC2s) modulate inflammatory and allergic responses, but their function in cancer immunity is still unclear. Here the authors show that, in acute promyelocytic leukaemia, tumour-activated ILC2s secrete IL-13 to induce myeloid-derived suppressor cells and support tumour growth.

Leukemias are routinely sub-typed for risk/outcome prediction and therapy choice using acquired mutations and chromosomal rearrangements. Down syndrome acute lymphoblastic leukemia (DS‐ALL) is characterized by high frequency of CRLF2 ‐rearrangements, JAK2 ‐mutations, or RAS‐pathway mutations. Intriguingly, JAK2 and RAS -mutations are mutually exclusive in leukemic sub‐clones, causing dichotomy in therapeutic target choices. We prove in a cell model that elevated CRLF2 in combination with constitutionally active JAK2 is sufficient to activate wtRAS. On primary clinical DS‐ALL samples, we show that wtRAS-activation is an obligatory consequence of mutated/hyperphosphorylated JAK2. We further prove that CRLF2-ligand TSLP boosts the direct binding of active PTPN11 to wtRAS, providing the molecular mechanism for the wtRAS activation. Pre‐inhibition of RAS or PTPN11, but not of PI3K or JAK‐signaling, prevented TSLP‐induced RAS‐GTP boost. Cytotoxicity assays on primary clinical DS‐ALL samples demonstrated that, regardless of mutation status, high-risk leukemic cells could only be killed using RAS‐inhibitor or PTPN11-inhibitor, but not PI3K/JAK‐inhibitors, suggesting a unified treatment target for up to 80% of DS‐ALL. Importantly, protein activities-based principal-component-analysis multivariate clusters analyzed for independent outcome prediction using Cox proportional-hazards model showed that protein‐activity (but not mutation-status) was independently predictive of outcome, demanding a paradigm-shift in patient‐stratification strategy for precision therapy in high-risk ALL.

BCL2‐associated athanogene‐1 (BAG1) is a multi‐functional protein that is found deregulated in several solid cancers and in paediatric acute myeloid leukaemia. The investigation of BAG1 isoforms expression and intracellular localization in B‐cell acute lymphoblastic leukaemia (B‐ALL) patient‐derived specimens revealed that BAG1 levels decrease during disease remission, compared to diagnosis, but drastically increase at relapse. In particular, at diagnosis both BAG1‐L and BAG1‐M isoforms are mainly nuclear, while during remission the localization pattern changes, having BAG1‐M almost exclusively in the cytosol indicating its potential cytoprotective role in B‐ALL. In addition, knockdown of BAG1/BAG3 induces cell apoptosis and G1‐phase cell cycle arrest and, more intriguingly, shapes cell response to chemotherapy. BAG1‐depleted cells show an increased sensitivity to the common chemotherapeutic agents, dexamethasone or daunorubicin, and to the BCL2 inhibitor ABT‐737. Moreover, the BAG1 inhibitor Thio‐2 induces a cytotoxic effect on RS4;11 cells both in vitro and in a zebrafish xenograft model and strongly synergizes with pan‐BCL inhibitors. Collectively, these data sustain BAG1 deregulation as a critical event in assuring survival advantage to B‐ALL cells.

Children with Down syndrome (DS) and acute lymphoblastic leukaemia (ALL) have poorer survival and more relapses than non-DS children with ALL, highlighting an urgent need for deeper mechanistic understanding of DS–ALL. Here, using full-exome or cancer genes-targeted sequencing of 42 ALL samples from 39 DS patients, we uncover driver mutations in RAS, (KRAS and NRAS) recurring to a similar extent (15/42) as JAK2 (12/42) mutations or P2RY8-CRLF2 fusions (14/42). RAS mutations are almost completely mutually exclusive with JAK2 mutations ( P =0.016), driving a combined total of two-thirds of analysed cases. Clonal architecture analysis reveals that both RAS and JAK2 drove sub-clonal expansions primarily initiated by CRLF2 rearrangements, and/or mutations in chromatin remodellers and lymphocyte differentiation factors. Remarkably, in 2/3 relapsed cases, there is a switch from a primary JAK2- or PTPN11-mutated sub-clone to a RAS-mutated sub-clone in relapse. These results provide important new insights informing the patient stratification strategies for targeted therapeutic approaches for DS–ALL. For children with acute lymphoblastic leukaemia (ALL), those with Down syndrome (DS) have decreased survival compared with children without DS. Here, the authors use exome sequencing to characterise the mutational landscape of patients with both ALL and DS and highlight genes related to survival and relapse.

To induce and sustain the leukaemogenic process, MLL-AF4+ leukaemia seems to require very few genetic alterations in addition to the fusion gene itself. Studies of infant and paediatric patients with MLL-AF4+ B cell precursor acute lymphoblastic leukaemia (BCP-ALL) have reported mutations in KRAS and NRAS with incidences ranging from 25 to 50%. Whereas previous studies employed Sanger sequencing, here we used next generation amplicon deep sequencing for in depth evaluation of RAS mutations in 36 paediatric patients at diagnosis of MLL-AF4+ leukaemia. RAS mutations including those in small sub-clones were detected in 63.9% of patients. Furthermore, the mutational analysis of 17 paired samples at diagnosis and relapse revealed complex RAS clone dynamics and showed that the mutated clones present at relapse were almost all originated from clones that were already detectable at diagnosis and survived to the initial therapy. Finally, we showed that mutated patients were indeed characterized by a RAS related signature at both transcriptional and protein levels and that the targeting of the RAS pathway could be of beneficial for treatment of MLL-AF4+ BCP-ALL clones carrying somatic RAS mutations.

In the AIEOP-BFM 2000 trial, 15% of pediatric patients treated according to risk-adapted polychemotherapeutic regimens relapsed. The present study aimed to investigate the influence of GST-M1 and GST-T1 deletions on clinical outcome of children with acute lymphoblastic leukemia treated according to the AIEOP-BFM ALL 2000 study protocol. A novel-design, two-phase study was applied to select a subsample of 614 children to be genotyped for the deletions of GST genes. Cumulative incidence of relapse was then estimated by weighted Kaplan-Meier analysis, and the Cox model was applied to evaluate the effect of GST-M1 and GST-T1 isoenzyme deletions on relapse. No overall effect was found, but the GST-M1 deletion was associated with better clinical outcome within prednisone poor-responder patients (hazard ratio [HR]: 0.45; 95% CI: 0.23-0.91; p = 0.026), whereas the GST-T1 deletion was associated with worse outcome in the standard-risk group (HR: 4.62; 95% CI: 1.04-20.6; p = 0.045) and within prednisone good responders (HR: 1.62; 95% CI: 1.02-2.58; p = 0.041). Our results show that GST-M1 and GST-T1 homozygous deletions have opposite correlation with relapse, the former being protective and the latter unfavourable in specific subsets of acute lymphoblastic leukemia patients.

In the AIEOP-BFM 2000 trial, 15% of pediatric patients treated according to risk-adapted polychemotherapeutic regimens relapsed. The present study aimed to investigate the influence of and deletions on clinical outcome of children with acute lymphoblastic leukemia treated according to the AIEOP-BFM ALL 2000 study protocol. A novel-design, two-phase study was applied to select a subsample of 614 children to be genotyped for the deletions of genes. Cumulative incidence of relapse was then estimated by weighted Kaplan-Meier analysis, and the Cox model was applied to evaluate the effect of and isoenzyme deletions on relapse. No overall effect was found, but the deletion was associated with better clinical outcome within prednisone poor-responder patients (hazard ratio [HR]: 0.45; 95% CI: 0.23-0.91; p = 0.026), whereas the deletion was associated with worse outcome in the standard-risk group (HR: 4.62; 95% CI: 1.04-20.6; p = 0.045) and within prednisone good responders (HR: 1.62; 95% CI: 1.02-2.58; p = 0.041). Our results show that and homozygous deletions have opposite correlation with relapse, the former being protective and the latter unfavourable in specific subsets of acute lymphoblastic leukemia patients. Original submitted 1 August 2012; Revision submitted 27 September 2012

Background: Down syndrome acute lymphoblastic leukemia (DS‐ALL) is characterized by the high frequency of CRLF2‐rearrangements, JAK2-mutations, or RAS-pathway mutations. Intriguingly, JAK2 and RAS mutations are mutually exclusive in leukemic sub‐clones, causing dichotomy in therapeutic target choices. Results: Here we show that in primary leukemic cells from DS‐ALL, in the absence of RAS-mutations, wild-type (wt)RAS is active, and/or can be induced by the physiological ligand TSLP of the transmembrane-receptor CRLF2. We show active/inducible RAS in 14/20 (70%) of primary DS-ALL samples analyzed, 8 of which had no RAS-mutations, but 75% of those had either mutated or hyperphosphorylated JAK2. No wtRAS cases with mutated/hyperphosphorylated JAK2 were observed that lacked activated RAS protein. We prove in a cell model that elevated CRLF2 in combination with constitutionally active JAK2 is sufficient to activate wtRAS. We show that TSLP boosts the direct binding of active PTPN11 to wtRAS. Pre‐inhibition of RAS or PTPN11, but not of PI3K or JAK signaling, prevented TSLP‐induced RAS‐GTP boost. Using multivariate-clustering based on RAS‐activity/inducibility we show significant separation between standard‐risk and high‐risk DS‐ALL groups. Cox proportional-hazards model showed protein-activity (but not mutation status) as independently predictive of outcome. Conclusions: Our data indicate that RAS protein activity levels (and not JAK2/RAS mutation profiles), are predictive of outcome. Importantly, our data suggest that inhibition of RAS and direct RAS‐pathway components should be combined with PI3K/mTOR and/or JAK2 inhibitors for high-risk cases. Therapeutically this is relevant for >75% of DS‐ALL and our additional data suggest that it warrants further investigation in high-risk non‐DS-ALL.