A non-invasive approach to monitor chronic lymphocytic leukemia engraftment in a xenograft mouse model using ultra-small superparamagnetic iron oxide-magnetic resonance imaging (USPIO-MRI).

This work was supported by: Associazione Italiana Ricerca sul Cancro (AIRC) [Grant 5 x mille n.9980, (to M.F., F.M. and A. N.)]; AIRC I.G. [n. 14,326 (to M.F.)], [n.10136 and 16,722 (A.N.)], [n.15426 (to F.F.)]. AIRC and Fondazione CaRiCal co-financed Multi Unit Regional Grant 2014 [n.16695 (to F.M.)]. Italian Ministry of Health 5 × 1000 funds (to F.F). A.G R. was supported by Associazione Italiana contro le Leucemie-Linfomi-Mielomi (AIL) Cosenza - Fondazione Amelia Scorza (FAS). S.M. C.M., F.V., L. E., S. B., were supported by AIRC.Peer reviewedPostprin

Association between gene and miRNA expression profiles and stereotyped subset #4 B-cell receptor in chronic lymphocytic leukemia

In this study we investigated specific biological and clinical features associated with chronic lymphocytic leukemia (CLL) patients carrying stereotyped BCR subset #4 (IGHV4-34) among a prospective cohort of 462 CLL/MBL patients in early stage (Binet A). All subset #4 patients (n = 16) were characterized by the IGHV mutated gene configuration, and absence of unfavorable cytogenetic lesions, NOTCH1 or SF3B1 mutations. Gene and miRNA expression profiling evidenced that the leukemic cells of subset #4 cases showed significant downregulation of WDFY4, MF2A and upregulation of PDGFA, FGFR1 and TFEC gene transcripts, as well as the upregulation of miR-497 and miR-29c. The transfection of miR-497 mimic in primary leukemic CLL cells induced a downregulation of BCL2, a known validated target of this miRNA. Our data identify biological characteristics associated with subset #4 patients, providing further evidence for the putative role of BCR in shaping the features of the tumor cells in CLL

Insulin Growth Factor 1 Receptor Expression Is Associated with <i>NOTCH1</i> Mutation, Trisomy 12 and Aggressive Clinical Course in Chronic Lymphocytic Leukaemia

<div><p><i>IGF1R</i> is emerging as an important gene in the pathogenesis of many solid and haematological cancers and its over-expression has been reported as frequently associated with aggressive disease and chemotherapy resistance. In this study we performed an investigation of the role of <i>IGF1R</i> expression in a large and representative prospective series of 217 chronic lymphocytic leukaemia (CLL) patients enrolled in the multicentre O-CLL1 protocol (clinicaltrial.gov #NCT00917540). High <i>IGF1R</i> gene expression was significantly associated with <i>IGHV</i> unmutated (<i>IGHV</i>-UM) status (p<0.0001), high CD38 expression (p<0.0001), trisomy 12 (p<0.0001), and del(11)(q23) (p=0.014). Interestingly, higher <i>IGF1R</i> expression (p=0.002) characterized patients with <i>NOTCH1</i> mutation (c.7541_7542delCT), identified in 15.5% of cases of our series by next generation sequencing and ARMS-PCR. Furthermore, <i>IGF1R</i> expression has been proven as an independent prognostic factor associated with time to first treatment in our CLL prospective cohort. These data suggest that <i>IGF1R</i> may play an important role in CLL biology, in particular in aggressive CLL clones characterized by <i>IGHV</i>-UM, trisomy 12 and <i>NOTCH1</i> mutation.</p></div

Microenvironmental regulation of the IL-23R/IL-23 axis overrides chronic lymphocytic leukemia indolence

reserved36noAlthough the progression of chronic lymphocytic leukemia (CLL) requires the cooperation of the microenvironment, the exact cellular and molecular mechanisms involved are still unclear. We investigated the interleukin (IL)-23 receptor (IL-23R)/IL-23 axis and found that circulating cells from early-stage CLL patients with shorter time-to-treatment, but not of those with a more benign course, expressed a defective form of the IL-23R complex lacking the IL-12Rb1 chain. However, cells from both patient groups expressed the complete IL-23R complex in tissue infiltrates and could be induced to express the IL-12Rb1 chain when cocultured with activated T cells or CD40L+cells. CLL cells activated in vitro in this context produced IL-23, a finding that, together with the presence of IL-23 in CLL lymphoid tissues, suggests the existence of an autocrine/paracrine loop inducing CLL cell proliferation. Interference with the IL-23R/IL-23 axis using an anti-IL-23p19 antibody proved effective in controlling disease onset and expansion in xenografted mice, suggesting potential therapeutic strategies.mixedCutrona, Giovanna*; Tripodo, Claudio; Matis, Serena; Recchia, Anna Grazia; Massucco, Carlotta; Fabbi, Marina; Colombo, Monica; Emionite, Laura; Sangaletti, Sabina; Gulino, Alessandro; Reverberi, Daniele; Massara, Rosanna; Boccardo, Simona; De Totero, Daniela; Salvi, Sandra; Cilli, Michele; Pellicanò, Mariavaleria; Manzoni, Martina; Fabris, Sonia; Airoldi, Irma; Valdora, Francesca; Ferrini, Silvano; Gentile, Massimo; Vigna, Ernesto; Bossio, Sabrina; De Stefano, Laura; Palummo, Angela; Iaquinta, Giovanni; Cardillo, Martina; Zupo, Simonetta; Cerruti, Giannamaria; Ibatici, Adalberto; Neri, Antonino; Fais, Franco; Ferrarini, Manlio; Morabito, FortunatoCutrona, Giovanna; Tripodo, Claudio; Matis, Serena; Recchia, Anna Grazia; Massucco, Carlotta; Fabbi, Marina; Colombo, Monica; Emionite, Laura; Sangaletti, Sabina; Gulino, Alessandro; Reverberi, Daniele; Massara, Rosanna; Boccardo, Simona; De Totero, Daniela; Salvi, Sandra; Cilli, Michele; Pellicanò, Mariavaleria; Manzoni, Martina; Fabris, Sonia; Airoldi, Irma; Valdora, Francesca; Ferrini, Silvano; Gentile, Massimo; Vigna, Ernesto; Bossio, Sabrina; De Stefano, Laura; Palummo, Angela; Iaquinta, Giovanni; Cardillo, Martina; Zupo, Simonetta; Cerruti, Giannamaria; Ibatici, Adalberto; Neri, Antonino; Fais, Franco; Ferrarini, Manlio; Morabito, Fortunat

Cox multivariate analysis results considering only CLL patients.

<p>HR: hazard ratio. CI: confidence interval.</p><p>Cox multivariate analysis results considering only CLL patients.</p

Boxplot of <i>IGF1R</i> expression in patients stratified according to trisomy 12 and NOTCH1 mutation (mut: mutation; wt: wild-type; w/o: without).

<p><i>IGF1R</i> was significant higher among the NOTCH1 mut/trisomy12, NOTCH1 mut/NOtrisomy12 and NOTCH1,wd/trisomy12 compared to other patients (p = 0.0035, p = 0.0031 and p = 0.0002 respectively).</p