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Motlló C, Ribera JM, Morgades M, Granada I, Montesinos P, Brunet S, Bergua J, Tormo M, García-Boyero R, Sarrà J, Del Potro E, Grande C, Barba P, Bernal T, Amigo ML, Grau J, Cervera J, Feliu E

Frequency and prognostic significance of t(v;11q23)/KMT2A rearrangements in adult patients with acute lymphoblastic leukemia treated with risk-adapted protocols.

Leuk. Lymphoma Jan 2017, 58 (1) 145-152. Epub 27 Apr 2016
The karyotype is an important predictor of outcome in acute lymphoblastic leukemia (ALL). Rearrangements of the 11q23 region involving the KMT2A gene confer an unfavorable prognosis. Forty-six adult ALL patients from the PETHEMA Group treated with risk-adapted protocols, with t(v;11q23) were selected for this study. Complete response (CR) was attained in 38 patients; 25 remained in CR after consolidation. Twelve (48%) received allogeneic hematopoietic stem cell transplantation (HSCT) and 13 delayed intensification and maintenance. The 5-year CR duration probability was 37% (95% CI, 19%-55%). A trend for a longer CR duration was observed in patients undergoing HSCT vs. those receiving chemotherapy. The 5-year overall survival (OS) probability was 20% (95% CI, 5%-35%). The OS was better, albeit not significant, in patients with a MRD level <0.1% after induction (39% [95% CI, 14%-64%] vs. 13% [95% CI, 0%-36%]). Specific treatment approaches are required to improve the outcome of patients with KMT2A-rearrangements.
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Drusbosky L, Medina C, Martuscello R, Hawkins KE, Chang M, Lamba JK, Vali S, Kumar A, Singh NK, Abbasi T, Sekeres MA, Mallo M, Sole F, Bejar R, Cogle CR

Computational drug treatment simulations on projections of dysregulated protein networks derived from the myelodysplastic mutanome match clinical response in patients.

Leuk. Res. 6 Nov 2016, 52 1-7. Epub 6 Nov 2016
Although the majority of MDS patients fail to achieve clinical improvement to approved therapies, some patients benefit from treatment. Predicting patient response prior to therapy would improve treatment effectiveness, avoid treatment-related adverse events and reduce healthcare costs. Three separate cohorts of MDS patients were used to simulate drug response to lenalidomide alone, hypomethylating agent (HMA) alone, or HMA plus lenalidomide. Utilizing a computational biology program, genomic abnormalities in each patient were used to create an intracellular pathway map that was then used to screen for drug response. In the lenalidomide treated cohort, computer modeling correctly matched clinical responses in 37/46 patients (80%). In the second cohort, 15 HMA patients were modeled and correctly matched to responses in 12 (80%). In the third cohort, computer modeling correctly matched responses in 10/10 patients (100%). This computational biology network approach identified GGH overexpression as a potential resistance factor to HMA treatment and paradoxical activation of beta-catenin (through Csnk1a1 inhibition) as a resistance factor to lenalidomide treatment. We demonstrate that a computational technology is able to map the complexity of the MDS mutanome to simulate and predict drug response. This tool can improve understanding of MDS biology and mechanisms of drug sensitivity and resistance.
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Palau A, Mallo M, Palomo L, Rodríguez-Hernández I, Diesch J, Campos D, Granada I, Juncà J, Drexler HG, Solé F, Buschbeck M

Immunophenotypic, cytogenetic, and mutational characterization of cell lines derived from myelodysplastic syndrome patients after progression to acute myeloid leukemia.

Genes Chromosomes Cancer 17 Oct 2016, . Epub 17 Oct 2016
Leukemia cell lines have been widely used in the hematology field to unravel mechanistic insights and to test new therapeutic strategies. Myelodysplastic syndromes (MDS) comprise a heterogeneous group of diseases that are characterized by ineffective hematopoiesis and frequent progress to acute myeloid leukemia (AML). A few cell lines have been established from MDS patients after progression to AML but their characterization is incomplete. Here we provide a detailed description of the immunophenotypic profile of the MDS-derived cell lines SKK-1, SKM-1, F-36P; and MOLM-13. Specifically, we analyzed a comprehensive panel of markers that are currently applied in the diagnostic routine for myeloid disorders. To provide high-resolution genetic data comprising copy number alterations and losses of heterozygosity we performed whole genome single nucleotide polymorphism-based arrays and included the cell line OHN-GM that harbors the frequent chromosome arm 5q deletion. Furthermore, we assessed the mutational status of 83 disease-relevant genes. Our results provide a resource to the MDS and AML field that allows researchers to choose the best-matching cell line for their functional studies. © 2016 Wiley Periodicals, Inc.
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Montoro J, Robledo C, Zamora L, Valcárcel D, Ramos F

Calreticulin mutations are exceedingly rare in patients with myelodysplastic syndromes with myelofibrosis.

Ann. Hematol. 12 Oct 2016, . Epub 12 Oct 2016More information
Muñoz-López A, Romero-Moya D, Prieto C, Ramos-Mejía V, Agraz-Doblas A, Varela I, Buschbeck M, Palau A, Carvajal-Vergara X, Giorgetti A, Ford A, Lako M, Granada I, Ruiz-Xivillé N, Rodríguez-Perales S, Torres-Ruíz R, Stam RW, Fuster JL, Fraga MF, Nakanishi M, Cazzaniga G, Bardini M, Cobo I, Bayon GF, Fernandez AF, Bueno C, Menendez P

Development Refractoriness of MLL-Rearranged Human B Cell Acute Leukemias to Reprogramming into Pluripotency.

Stem Cell Reports 11 Oct 2016, 7 (4) 602-618. Epub 22 Sep 2016
Induced pluripotent stem cells (iPSCs) are a powerful tool for disease modeling. They are routinely generated from healthy donors and patients from multiple cell types at different developmental stages. However, reprogramming leukemias is an extremely inefficient process. Few studies generated iPSCs from primary chronic myeloid leukemias, but iPSC generation from acute myeloid or lymphoid leukemias (ALL) has not been achieved. We attempted to generate iPSCs from different subtypes of B-ALL to address the developmental impact of leukemic fusion genes. OKSM(L)-expressing mono/polycistronic-, retroviral/lentiviral/episomal-, and Sendai virus vector-based reprogramming strategies failed to render iPSCs in vitro and in vivo. Addition of transcriptomic-epigenetic reprogramming "boosters" also failed to generate iPSCs from B cell blasts and B-ALL lines, and when iPSCs emerged they lacked leukemic fusion genes, demonstrating non-leukemic myeloid origin. Conversely, MLL-AF4-overexpressing hematopoietic stem cells/B progenitors were successfully reprogrammed, indicating that B cell origin and leukemic fusion gene were not reprogramming barriers. Global transcriptome/DNA methylome profiling suggested a developmental/differentiation refractoriness of MLL-rearranged B-ALL to reprogramming into pluripotency.
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