Gachet S, El-Chaar T, Avran D, Genesca E, Catez F, Quentin S, Delord M, Thérizols G, Briot D, Meunier G, Hernandez L, Pla M, Smits WK, Buijs-Gladdines JG, Van Loocke W, Menschaert G, André-Schmutz I, Taghon T, Van Vlierberghe P, Meijerink JP, Baruchel A, Dombret H, Clappier E, Diaz JJ, Gazin C, de Thé H, Sigaux F, Soulier J
Deletion 6q Drives T-cell Leukemia Progression by Ribosome Modulation.
Cancer DiscovDec 2018, 8(12)1614-1631. Epub 28 Sep 2018
Deletion of chromosome 6q is a well-recognized abnormality found in poor-prognosis T-cell acute lymphoblastic leukemia (T-ALL). Using integrated genomic approaches, we identified two candidate haploinsufficient genes contiguous at 6q14,
Nagata Y, Narumi S, Guan Y, Przychodzen BP, Hirsch CM, Makishima H, Shima H, Aly M, Pastor V, Kuzmanovic T, Radivoyevitch T, Adema V, Awada H, Yoshida K, Li S, Sole F, Hanna R, Jha BK, LaFramboise T, Ogawa S, Sekeres MA, Wlodarski MW, Cammenga J, Maciejewski JP
Germline loss of function SAMD9 and SAMD9L alterations in adult myelodysplastic syndromes
Miyazaki Y, Tuechler H, Sanz G, Schanz J, Garcia-Manero G, Solé F, Bennett JM, Bowen D, Fenaux P, Dreyfus F, Kantarjian H, Kuendgen A, Malcovati L, Cazzola M, Cermak J, Fonatsch C, Le Beau MM, Slovak ML, Santini V, Lübbert M, Maciejewski J, Machherndl-Spandl S, Magalhaes SMM, Pfeilstöcker M, Sekeres MA, Sperr WR, Stauder R, Tauro S, Valent P, Vallespi T, van de Loosdrecht AA, Germing U, Haase D, Greenberg PL
Differing clinical features between Japanese and Caucasian patients with myelodysplastic syndromes: Analysis from the International Working Group for Prognosis of MDS.
Leuk. Res.Oct 2018, 7351-57. Epub 6 Sep 2018
Clinical features of myelodysplastic syndromes (MDS) could be influenced by many factors, such as disease intrinsic factors (e.g., morphologic, cytogenetic, molecular), extrinsic factors (e.g, management, environment), and ethnicity. Several previous studies have suggested such differences between Asian and European/USA countries. In this study, to elucidate potential differences in primary untreated MDS between Japanese (JPN) and Caucasians (CAUC), we analyzed the data from a large international database collected by the International Working Group for Prognosis of MDS (300 and 5838 patients, respectively). JPN MDS were significantly younger with more severe cytopenias, and cytogenetic differences: less del(5q) and more +1/+1q, -1/del(1p), der(1;7), -9/del(9q), del(16q), and del(20q). Although differences in time to acute myeloid leukemia transformation did not occur, a significantly better survival in JPN was demonstrated, even after the adjustment for age and FAB subtypes, especially in lower, but not in higher prognostic risk categories. Certain clinical factors (cytopenias, blast percentage, cytogenetic risk) had different impact on survival and time to transformation to leukemia between the two groups. Although possible confounding events (e.g., environment, diet, and access to care) could not be excluded, our results indicated the existence of clinically relevant ethnic differences regarding survival in MDS between JPN and CAUC patients. The good performance of the IPSS-R in both CAUC and JP patients underlines that its common risk model is adequate for CAUC and JP.
Schanz J, Solé F, Mallo M, Luño E, Cervera J, Granada I, Hildebrandt B, Slovak ML, Ohyashiki K, Fonatsch C, Pfeilstöcker M, Nösslinger T, Valent P, Giagounidis A, Aul C, Lübbert M, Stauder R, Krieger O, Le Beau MM, Bennett JM, Greenberg P, Germing U, Haase D
Clonal architecture in patients with myelodysplastic syndromes and double or minor complex abnormalities: Detailed analysis of clonal composition, involved abnormalities, and prognostic significance.
The study analyzes the clonal architecture and the abnormalities involved in a series of 191 patients with myelodysplastic syndromes (MDS) and 2-3 clonal abnormalities. All patients were extracted from an international database. The patients were classified into six clonal subtypes (2A-3C) based on the number of abnormalities and the presentation of unrelated clones (UC) and/or a clonal evolution. UC were detected in 23/191 patients (12%). The composition of UC showed great variability. The only recurrent combination of abnormalities was del(5q) and + 8 in 8 of 23 patients (35%). In patients with clonal evolution, the clone size of the primary and secondary clone varied: Patients with -7 and + 8 in the primary clone showed a larger primary and a smaller secondary clone (-7: median 74% vs 10%; +8 73% vs 18%) while patients with del(5q) in the primary clone showed a smaller primary and a larger secondary clone (33% vs 61%). Univariate and multivariate analyses showed no significant differences regarding overall or AML-free survival between the clonal subtypes. Only the subtype 3C (3 abnormalities and clonal evolution) was an independent risk factor for developing AML (Hazard Ratio 5.5 as compared to subtype 2A, P < .05). Finally, our study confirms that the number of abnormalities clearly defines a significant risk factor for overall- as well as AML-free survival. Importantly, in patients with more than one clone, the calculation of the number of abnormalities in the entire sample instead of the number of abnormalities per clone allows a higher prognostic accuracy.
Banús-Mulet A, Etxabe A, Cornet-Masana JM, Torrente MÁ, Lara-Castillo MC, Palomo L, Nomdedeu M, Díaz-Beyá M, Solé F, Nomdedeu B, Esteve J, Risueño RM
Serotonin receptor type 1B constitutes a therapeutic target for MDS and CMML.
Sci Rep17 Sep 2018, 8(1)13883. Epub 17 Sep 2018
Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) are chronic myeloid clonal neoplasms. To date, the only potentially curative therapy for these disorders remains allogeneic hematopoietic progenitor cell transplantation (HCT), although patient eligibility is limited due to high morbimortality associated with this procedure coupled with advanced age of most patients. Dopamine receptors (DRs) and serotonin receptors type 1 (HTR1s) were identified as cancer stem cell therapeutic targets in acute myeloid leukemia. Given their close pathophysiologic relationship, expression of HTR1s and DRs was interrogated in MDS and CMML. Both receptors were differentially expressed in patient samples compared to healthy donors. Treatment with HTR1B antagonists reduced cell viability. HTR1 antagonists showed a synergistic cytotoxic effect with currently approved hypomethylating agents in AML cells. Our results suggest that HTR1B constitutes a novel therapeutic target for MDS and CMML. Due to its druggability, the clinical development of new regimens based on this target is promising.
Lo Re O, Douet J, Buschbeck M, Fusilli C, Pazienza V, Panebianco C, Castracani CC, Mazza T, Li Volti G, Vinciguerra M
Histone variant macroH2A1 rewires carbohydrate and lipid metabolism of hepatocellular carcinoma cells towards cancer stem cells.
Epigenetics30 Aug 2018, . Epub 30 Aug 2018
Hepatocellular carcinomas (HCCs) contain a sub-population of cancer stem cells (CSCs) that are responsible for tumor relapse, metastasis, and chemoresistance. We recently showed that loss of macroH2A1, a variant of the histone H2A and an epigenetic regulator of stem-cell function, in HCC leads to CSC-like features such as resistance to chemotherapeutic agents and growth of large and relatively undifferentiated tumors in xenograft models. These HCC cells silenced for macroH2A1 also exhibited stem-like metabolic changes consistent with enhanced glycolysis. However, there is no consensus as to the metabolic characteristics of CSCs that render them adaptable to microenvironmental changes by conveniently shifting energy production source or by acquiring intermediate metabolic phenotypes. Here, we assessed long-term proliferation, energy metabolism, and central carbon metabolism in human hepatoma HepG2 cells depleted in macroH2A1. MacroH2A1-depleted HepG2 cells were insensitive to serum exhaustion and showed two distinct, but interdependent changes in glucose and lipid metabolism in CSCs: (1) massive upregulation of acetyl-coA that is transformed into enhanced lipid content and (2) increased activation of the pentose phosphate pathway, diverting glycolytic intermediates to provide precursors for nucleotide synthesis. Integration of metabolomic analyses with RNA-Seq data revealed a critical role for the Liver X Receptor pathway, whose inhibition resulted in attenuated CSCs-like features. These findings shed light on the metabolic phenotype of epigenetically modified CSC-like hepatic cells, and highlight a potential approach for selective therapeutic targeting.
Avivi I, Boumendil A, Finel H, Nagler A, de Sousa AB, Santasusana JMR, Vandenberghe E, Afanasyev B, Bordessoule D, Moraleda JM, Garcia EC, Pohlreich D, Garcia GG, Thomson K, Or R, Beelen D, Zuffa E, Giebel S, Berthou C, Salles G, Melpignano A, Montoto S, Dreger P
Autologous stem cell transplantation for primary mediastinal B-cell lymphoma: long-term outcome and role of post-transplant radiotherapy. A report of the European Society for Blood and Marrow Transplantation.
Bone Marrow Transplant.Aug 2018, 53(8)1001-1009. Epub 20 Feb 2018
The purpose of this retrospective registry study was to investigate the outcome of autoSCT for primary mediastinal B-cell lymphoma (PMBCL) in the rituximab era, including the effects of eventual post-transplant radiotherapy (RT) consolidation. Patients with PMBCL aged between 18 and 70 years who were treated with a first autoSCT between 2000 and 2012 and registered with the EBMT were eligible. Eighty-six patients with confirmed PMBCL and the full data set required for this analysis were evaluable. Sixteen patients underwent autoSCT in remission after first-line therapy (CR/PR1), 44 patients were transplanted with chemosensitive relapsed or primary refractory disease (CR/PR >1), and 24 patients were chemorefractory at the time of autoSCT. With a median follow-up of 5 years, 3-year estimates of relapse incidence, progression-free survival, and overall survival were 6%, 94%, and 100% for CR/PR1; 31%, 64%, and 85% for CR/PR >1; and 52%, 39%, and 41% for REF, respectively. Whilst there was no significant benefit of post-transplant RT in the CR/PR >1 group, RT could completely prevent disease recurrence post d100 in the refractory group. In conclusion, autoSCT with or without consolidating RT is associated with excellent outcome in chemoimmunotherapy-sensitive PMBCL, whereas its benefits seem to be limited in chemoimmunotherapy-refractory disease.
Buatois V, Johnson Z, Salgado-Pires S, Papaioannou A, Hatterer E, Chauchet X, Richard F, Barba L, Daubeuf B, Cons L, Broyer L, D'Asaro M, Matthes T, LeGallou S, Fest T, Tarte K, Clarke Hinojosa RK, Genescà Ferrer E, Ribera JM, Dey A, Bailey K, Fielding AK, Eissenberg L, Ritchey J, Rettig M, DiPersio JF, Kosco-Vilbois MH, Masternak K, Fischer N, Shang L, Ferlin WG
Preclinical Development of a Bispecific Antibody that Safely and Effectively Targets CD19 and CD47 for the Treatment of B-Cell Lymphoma and Leukemia.
Mol. Cancer Ther.Aug 2018, 17(8)1739-1751. Epub 9 May 2018
CD47, an ubiquitously expressed innate immune checkpoint receptor that serves as a universal "don't eat me" signal of phagocytosis, is often upregulated by hematologic and solid cancers to evade immune surveillance. Development of CD47-targeted modalities is hindered by the ubiquitous expression of the target, often leading to rapid drug elimination and hemotoxicity including anemia. To overcome such liabilities, we have developed a fully human bispecific antibody, NI-1701, designed to coengage CD47 and CD19 selectively on B cells. NI-1701 demonstrates favorable elimination kinetics with no deleterious effects seen on hematologic parameters following single or multiple administrations to nonhuman primates. Potent
Genescà E, Lazarenkov A, Morgades M, Berbis G, Ruíz-Xivillé N, Gómez-Marzo P, Ribera J, Juncà J, González-Pérez A, Mercadal S, Guardia R, Artola MT, Moreno MJ, Martínez-López J, Zamora L, Barba P, Gil C, Tormo M, Cladera A, Novo A, Pratcorona M, Nomdedeu J, González-Campos J, Almeida M, Cervera J, Montesinos P, Batlle M, Vives S, Esteve J, Feliu E, Solé F, Orfao A, Ribera JM
Frequency and clinical impact of CDKN2A/ARF/CDKN2B gene deletions as assessed by in-depth genetic analyses in adult T cell acute lymphoblastic leukemia.
Recurrent deletions of the CDKN2A/ARF/CDKN2B genes encoded at chromosome 9p21 have been described in both pediatric and adult acute lymphoblastic leukemia (ALL), but their prognostic value remains controversial, with limited data on adult T-ALL. Here, we investigated the presence of homozygous and heterozygous deletions of the CDKN2A/ARF and CDKN2B genes in 64 adult T-ALL patients enrolled in two consecutive trials from the Spanish PETHEMA group. Alterations in CDKN2A/ARF/CDKN2B were detected in 35/64 patients (55%). Most of them consisted of 9p21 losses involving homozygous deletions of the CDKNA/ARF gene (26/64), as confirmed by single nucleotide polymorphism (SNP) arrays and interphase fluorescence in situ hybridization (iFISH). Deletions involving the CDKN2A/ARF/CDKN2B locus correlated with a higher frequency of cortical T cell phenotype and a better clearance of minimal residual disease (MRD) after induction therapy. Moreover, the combination of an altered copy-number-value (CNV) involving the CDKN2A/ARF/CDKN2B gene locus and undetectable MRD (≤ 0.01%) values allowed the identification of a subset of T-ALL with better overall survival in the absence of hematopoietic stem cell transplantation.