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Introduction: Outcomes for silver coated megaprostheses (SC-MP) used in cases of end-stage periprosthetic joint infection (PJI) have not been clearly defined. Although attractive, concerns over implant longevity and the risk of infection relapse exist among the scientific community. Therefore, we sought to investigate the effect of silver coating in lower-extremity MPs used in such difficult-to-treat scenarios. The study's primary hypothesis was that the periprosthetic infection control rate would be higher in patients with silver-coated implants. Materials and methods: Non-interventional retrospective study with a historical comparison group. We identified all consecutive end-stage hip and knee PJI cases at our center managed with exchange arthroplasty using a silver-coated megaprosthesis from January 2016 to March 2021, these cases were compared with a historical cohort of end-stage PJI cases managed with uncoated megaprostheses. The main outcome studied was infection control rate. Secondarily, we analyzed the short-to-medium-term survivorship of this type of silver-coated implant. Results: Fifty-nine megaprostheses used in cases of end-stage PJI were included in this study. We identified 30 cases of chronic hip or knee PJI in which a silver-coated modular megaprosthesis was implanted. Our non-coated megaprosthesis (NC-MP) historical group included 29 patients. Both groups had similar demographic characteristics. We found no statistically significant differences in infection control rate (80% vs. 82.8%, p = 0.47) or implant survivorship (90% vs. 89.65%, p = 1) after a mean follow-up for SC-MP of 46.43 months, and 48 months for the non-coated MP group. In relapsed cases, there were no differences in infection eradication after DAIR (66% SC-MP vs. 60% NC-MP success rate, p = 1). During the follow-up we observed one case of skin argyria without further repercussion. Conclusion: We were unable to confirm our initial hypothesis that use of silver-coated implants in end-stage PJI scenarios may be associated with better outcomes in terms of infection control or implant survivorship. [ABSTRACT FROM AUTHOR]

Purpose Most patients with acute myeloid leukemia ( AML) and genetic rearrangements involving the core binding factor ( CBF) have favorable prognosis. In contrast, a minority of them still have a high risk of leukemia recurrence. This study investigated the adverse features of CBF AML that could justify investigational therapeutic approaches. Patients and methods One hundred and fifty patients (median age 42 yr, range 16-69) with CBF AML ( RUNX1- RUNX1T1 n = 74; CBFB- MYH11 n = 76) were prospectively enrolled into two consecutive CETLAM protocols at 19 Spanish institutions. Main clinic and biologic parameters were analyzed in the whole series. In non-selected cases with available DNA samples, the impact of molecular characterization and minimal residual disease ( MRD) was also studied. Results Overall, complete remission ( CR) rate was 89% (94% in ≤50 yr old and 72% in >50 yr, P = 0.002). At 5 yr, cumulative incidence of relapse ( CIR) was 26 ± 1%, disease-free survival ( DFS) 62 ± 6%, and overall survival ( OS) 66 ± 4%. In multivariate analyses, leukocyte count above 20 × 109/L, BAALC over-expression, and high copy numbers of RUNX1- RUNXT1 or CBFB- MYH11 after induction chemotherapy ( CT) led to increased relapse rate. Regarding OS, age >50 yr, leukocyte count above 20 × 109/L, and increased MN1 expression were adverse features. Conclusion Age, leukocyte counts, BAALC, and MN1 gene expressions as well as high copy numbers of RUNX1- RUNXT1 or CBFB- MYH11 after induction chemotherapy are useful tools to predict the outcome and should be considered for risk-adapted therapy. [ABSTRACT FROM AUTHOR]

Describes the p53 mutation in a case of blastic transformation of follicular lymphoma (FL) with double bcl-2 rearrangement. Description of a third breakpoint at the 5' part of the bcl-2 locus; Molecular analysis of an FL transformed into a blastic phase unresponsive to chemotherapy; Overexpression of p53 and bcl-2 on the affected sites.

Summary: Chronic myelomonocytic leukaemia (CMML) is a rare haematological disorder characterized by monocytosis and dysplastic changes in myeloid cell lineages. Accurate risk stratification is essential for guiding treatment decisions and assessing prognosis. This study aimed to validate the Artificial Intelligence Prognostic Scoring System for Myelodysplastic Syndromes (AIPSS‐MDS) in CMML and to assess its performance compared with traditional scores using data from a Spanish registry (n = 1343) and a Taiwanese hospital (n = 75). In the Spanish cohort, the AIPSS‐MDS accurately predicted overall survival (OS) and leukaemia‐free survival (LFS), outperforming the Revised‐IPSS score. Similarly, in the Taiwanese cohort, the AIPSS‐MDS demonstrated accurate predictions for OS and LFS, showing superiority over the IPSS score and performing better than the CPSS and molecular CPSS scores in differentiating patient outcomes. The consistent performance of the AIPSS‐MDS across both cohorts highlights its generalizability. Its adoption as a valuable tool for personalized treatment decision‐making in CMML enables clinicians to identify high‐risk patients who may benefit from different therapeutic interventions. Future studies should explore the integration of genetic information into the AIPSS‐MDS to further refine risk stratification in CMML and improve patient outcomes. [ABSTRACT FROM AUTHOR]

Treatment of chronic lymphocytic leukemia (CLL) has dramatically evolved over the last decades thanks to the introduction of targeted therapies. We aimed to describe retrospectively the evolution in the frontline prescription in the CLL patients from our institution. As a secondary objective, the impact of frontline therapy on the time-to-next-treatment (TTNT) and overall survival (OS). After a median of 6.4 years (0.1–36.4) of follow-up from diagnosis, 323 of 780 CLL patients (41.4%) required therapy. Alkylating agents in monotherapy (chlorambucil) were the most used until 2012, and from then, chemoimmunotherapy. Since 2018, targeted therapies were the most common therapeutic strategy (74.1%). Patients who received targeted therapies had significantly longer TTNT compared to other regimens. In the multivariable analyses, mutated IGHV genes targeted therapies and chemoimmunotherapy regimens were related to longer TTNT, and sex female, age younger than 65, and mutated IGHV genes were associated with better OS. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "MOPP, ABVD, or Both to Treat Hodgkin's Disease," by G.P. Canellos in the November 19, 1992 issue.

Dear Editor, Acute promyelocytic leukaemia (APL) is characterized by the presence of the t(15;17) chromosomal translocation that generates the I PML-RARA i fusion gene [[1]]. To determine the sensitivity for detecting each breakpoint by PCR, leukaemic DNA samples were suspended at 20 ng/ L and iteratively diluted tenfold to a dilution of 1:10,000 into equimolar (20 ng/ L) pooled normal blood DNA from 10 healthy subjects. Here, to investigate whether I PML-RARA i is detectable in the blood before APL onset, we study four APL cases with blood DNA available, from the same individual, 2-12 years before diagnosis. [Extracted from the article]

Summary: In the European LeukemiaNet favourable risk category, allogeneic haematopoietic stem cell transplantation (alloSCT) is not indicated in first complete remission for patients with acute myeloid leukaemia (AML) with NPM1 mutations (ELNfav NPM1 AML), although a proportion of these patients will relapse. Given the prognostic importance of measurable residual disease (MRD), CETLAM‐12 considered a pre‐emptive intervention in patients with molecular failure (MF). We analyzed 110 ELNfav NPM1 AML patients achieving complete remission (CR) after induction chemotherapy. Two‐year cumulative incidence of relapse (CIR), overall survival (OS) and leukaemia‐free survival (LFS) were 17%, 81·5% and 82%, respectively. Forty‐six patients required additional therapy for MF (n = 33) or haematological relapse (HemR; n = 13), resulting in a molecular LFS (molLFS) and a cumulative incidence of MF at two years of 61% and 38% respectively. Two‐year OS for these 46 patients was 66%, with a different outcome between patients with MF (86%) and HemR (42%) (P = 0·002). Quantitative NPM1 detection at different timepoints was predictive of molLFS; an MRD ratio (NPM1mut/ABL1 × 100) cut‐off of 0·05 after first consolidation identified two cohorts with a two‐year molLFS of 77% and 40% for patients below and above 0·05, respectively. In conclusion, MRD‐based pre‐emptive intervention resulted in a favourable outcome for ELNfav NPM1 AML patients. [ABSTRACT FROM AUTHOR]

Background: In chronic lymphocytic leukemia, a better understanding of leukemic cell characteristics after treatment would help to design specific therapeutic approaches aimed at preventing clinical relapse. Gene arrays have become a powerful approach to perform gene expression profiling; nevertheless, to work with residual cells entails an intensive labor. The aim of this study was to set forth an effective gene expression approach to analyze residual leukemic cells. Methods: Leukocytes from CLL patient's samples were sorted by flow cytometry using a 6‐color panel. The quality and quantity of RNA isolated from different inputs of cells were compared by two silica column protocols: RNeasy Micro and RNeasy Mini. RNA amplifications were carried out according to two manufacturer's protocols: Ovation Pico SL and Ovation Pico WTA. A total of 3.5 μg of cDNA was labeled and hybridized to Human Gene 2.0 ST arrays. Results: RNA extracted from low number of input cells by RNeasy Micro showed similar RNA integrity number to that obtained from RNeasy Mini; however, the RNA quantity was higher using the RNeasy Micro Kit. In addition, those RNA samples obtained with RNeasy Micro and amplified with Ovation Pico WTA showed good quality to proceed for a gene array study, independently of the number of input cells (range: 1 × 104‐5 × 105 cells). Conclusions: We observed that this workflow is a feasible approach to obtain genomic material extracted from leukemic cells as little as 1 × 104 cells and it can be useful to carry out gene expression profile experiments to characterize residual leukemic cells in chronic lymphocytic leukemia. [ABSTRACT FROM AUTHOR]

Summary: The prognostic significance of low‐hypodiploidy has not been extensively evaluated in minimal residual disease (MRD)‐oriented protocols for adult acute lymphoblastic leukaemia (ALL). We analysed the outcome of hypodiploid adult ALL patients treated within Programa Español de Tratamientos en Hematología (PETHEMA) protocols. The 5‐year cumulative incidence of relapse (CIR) of low‐hypodiploid B‐cell precursor (BCP)‐ALL was significantly higher than that of high‐hypodiploids (52% vs. 12%, P = 0.013). Low‐hypodiploid BCP‐ALL patients aged ≤35 years showed superior survival (71% vs. 21%, P = 0.026) and lower 5‐year CIR (17% vs. 66%, P = 0.090) than low‐hypodiploids aged >35 years. Older adults and elderly low‐hypodiploid BCP‐ALL patients show dismal prognosis although achieving an end‐induction good MRD response. [ABSTRACT FROM AUTHOR]

Out of 956, there were 95 (10%) CD56+ APL patients treated with PETHEMA ATRA and chemotherapy. CD56+ expression was associated with high WBC, BCR3 isoform, and co-expression of CD2, CD34, CD7, HLA-DR, CD15, and CD117 antigens. CD56+ vs CD56- APL presented higher induction death rate (16% vs 8%, p =.02) and 5-years cumulative incidence of relapse (33% versus 10%, p =.006), irrespectively of the Sanz score (low-risk 47% versus 5%, p <.001; intermediate 23% versus 7%, p <.001; and high-risk 42% versus 21%, p =.007). In the multivariate analysis, CD56 + (p <.0001), higher relapse-risk score (p =.001), and male gender (p =.05) retained the independent predictive value. CD56+ APL also showed a greater risk of CNS relapse (6% versus 1%, p <.001) and lower 5-year OS (75% versus 83%, p =.003). The AIDA-based LPA2012 trial, with an intensified consolidation schedule for CD56+ APL, will elucidate whether an intensified consolidation schedule could mitigate the relapse rate in this setting. [ABSTRACT FROM AUTHOR]

In intermediate-risk cytogenetic acute myeloid leukemia (IRC-AML) patients, novel biomarkers to guide post-remission therapy are needed. We analyzed with high-density arrays 40 IRC-AML patients who received a non-allogeneic hematopoietic stem-cell transplantation-based post-remission therapy, and identified a signature that correlated with early relapse. Subsequently, we analyzed selected 187 genes in 49 additional IRC-AML patients by RT-PCR. BAALC, MN1, SPARC and HOPX overexpression correlated to refractoriness. BAALC or ALDH2 overexpression correlated to shorter overall survival (OS) (5-year OS: 33 ± 8.6% vs. 73.7 ± 10.1%, p = .006; 32 ± 9.3% vs. 66.4 ± 9.7%, p = .016), whereas GPR44 or TP53INP1 overexpression correlated to longer survival (5-year OS: 66.7 ± 10.3% vs. 35.4 ± 9.1%, p = .04; 58.3 ± 8.2% vs. 23.1 ± 11.7%, p = .029). A risk-score combining these four genes expression distinguished low-risk and high-risk patients (5-year OS: 79 ± 9% vs. 30 ± 8%, respectively; p = .001) in our cohort and in an independent set of patients from a public repository. Our 4-gene signature may add prognostic information and guide post-remission treatment in IRC-AML patients. [ABSTRACT FROM AUTHOR]

In normal B-cells, B-cell antigen receptor (BCR) signaling can be negatively regulated by the low-affinity receptor FcγRIIb (CD32b). To better understand the role of FcγRIIb in chronic lymphocytic leukemia (CLL), we correlated its expression on 155 samples from newly-diagnosed Binet A patients with clinical characteristics and outcome. FcγRIIb expression was similar in normal B-cells and leukemic cells, this being heterogenous among patients and within CLL clones. FcγRIIb expression did not correlate with well known prognostic markers [disease stage, serum beta-2 microglobulin (B2M), IGHV mutational status, expression of ZAP-70 and CD38, and cytogenetics] except for a weak concordance with CD49d. Moreover, patients with low FcγRIIb expression (69/155, 44.5%) required therapy earlier than those with high FcγRIIb expression (86/155, 55.5%) (median 151.4 months vs. not reached; p=.071). These results encourage further investigation on the role of FcγRIIb in CLL biology and prognostic significance in larger series of patients. [ABSTRACT FROM AUTHOR]

Venous thromboembolism (VTE) is a common disease that involves the interaction of genetic and environmental risk factors. Previous studies have estimated a heritability of approximately 60% for the risk of VTE. Using variance analysis, intermediate phenotypes related to thrombosis have been used to identify genetic risk factors. Erythrocyte intermediate phenotypes are good candidates for VTE risk factors. We investigated the relationship of erythrocyte-related phenotypes with the risk of VTE. Our study used the Genetic Analysis of Idiopathic Thrombophilia 2 (GAIT2 Project) sample, which consisted of 35 extended pedigrees (including a total of 935 individuals). The sample had 120 subjects with thromboembolism (86 with VTE, 47 with arterial thrombosis and 13 with both). The following risk factors were evaluated: Red blood cell parameters, reticulocytes, serum iron, total iron binding capacity, serum ferritin, serum transferrin receptor (STFR), and haptoglobin. Using the variance component method, heritability (h 2 ) and the phenotypic, genetic and environmental correlations with VTE were estimated. The h 2 of VTE was 0.67. Most erythrocyte parameters showed significantly high h 2 . In addition, VTE was genetically correlated with: hematocrit (ρ G = 0.52, p = 0.01), red blood cell distribution width (RDW) (ρ G = 0.28, p = 0.05), immature reticulocyte fraction (IRF) (ρ G = 0.45, p = 0.008), transferrin saturation index (ρ G = − 0.7, p = 0.05), and STFR (ρ G = 0.4, p = 0.006). In conclusion, a genetic relationship between erythrocyte intermediate phenotypes and VTE was demonstrated. Also, we identified 5 phenotypes as risk factors. These phenotypes are useful in the search for genes that affect VTE. [ABSTRACT FROM AUTHOR]

Background: Some copy number alterations (CNAs) have independent prognostic significance for adults with acute lymphoblastic leukemia (ALL).Methods: This study analyzed via multiplex ligation-dependent probe amplification the frequency and prognostic impact of CNAs of 12 genetic regions in 142 adolescents and adults with de novo precursor B-cell ALL.Results: The cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) deletion (59 of 142 or 42%) was the most frequent CNA, and it was followed by Ikaros family zinc finger 1 (IKZF1) losses (49 of 142 or 35%). IKZF1 deletions were more prevalent in Philadelphia chromosome (Ph)-positive ALL and were associated with advanced age and high white blood cell (WBC) counts. The multivariate analysis showed that advanced age and early B-cell factor 1 (EBF1) deletions were associated with chemotherapy resistance in both the whole series (hazard ratios, 0.949 and 0.135, respectively) and the Ph-negative subgroup (hazard ratios, 0.946 and 0.118, respectively). High WBC counts and focal IKZF1 deletions correlated with disease recurrence (hazard ratios, 1.005 and 1.869, respectively), whereas advanced age and CDKN2A/B losses influenced overall survival in both the whole series (hazard ratios, 1.038 and 2.545, respectively) and the Ph-negative subgroup (hazard ratios, 1.044 and 2.105, respectively).Conclusions: Deletions of EBF1, IKZF1, and CDKN2A/B have an independent adverse prognosis for adolescents and adults with B-precursor ALL, and this suggests that these CNAs should be included in the initial risk assessment of ALL. [ABSTRACT FROM AUTHOR]

Introduction Platelets play a significant role in arterial thrombosis and are involved also in venous thrombosis. The genetic determinants of several platelet-related phenotypes have been studied previously. However, to the best of our knowledge, the genetic determinants of other platelet phenotypes have not been reported such as platelet-large-cell ratio (P-LCR) index, immature platelet fraction (IPF) parameters and overall platelet function measured through the PFA-100 system. Materials and Methods As part of the GAIT-2 (Genetic Analysis of Idiopathic Thrombophilia 2) Project, 935 individuals from 35 large Spanish families, ascertained through a proband with thrombophilia, were studied. Using variance component methods, implemented in the SOLAR package, the heritability of the following sets of platelet-related phenotypes was determined: platelet count and indices, IPF, and platelet function. Results and Conclusions High heritabilities of the platelet count and index phenotypes (from 0.41 to 0.64) were found, especially for those related to platelet volume. The heritabilities of the IPF phenotypes, as a measure of platelet turnover, were the highest (from 0.65 to 0.69). The heritabilities of the platelet function phenotypes were high also (0.45 and 0.62). The covariate age influenced all of the platelet phenotypes. Smoking influenced the platelet indices related to platelet volume and all the IPF phenotypes. Venous thrombosis showed a heritability of 0.67. We did not find a genetic correlation between any of the platelet-related phenotypes and venous thrombosis. The high heritabilities found for all of the platelet phenotypes provid promising data for the identification of new genes that underly these phenotypes. [ABSTRACT FROM AUTHOR]

Genetic lesions and B-cell receptor (BCR) signaling are both oncogenic drivers in chronic lymphocytic leukemia (CLL). However, scant data are available on preferential associations between specific genetic alterations and stereotyped BCR subsets. By analyzing 1419 cases, 2 CLL subsets (2 and 8) harboring stereotyped BCR are enriched in specific molecular alterations influencing disease course. SF3B1 mutations are the genetic hallmark of IGHV3-21-CLL belonging to subset 2 (52%) but are evenly represented in nonstereotyped IGHV3-21-CLL. Trisomy 12 (87%) and NOTCH1 mutations (62%) characterize IGHV4-39-CLL belonging to subset 8 but occur with the expected frequency in IGHV4-39-CLL with heterogeneous BCR. Clinically, co-occurrence of SF3B1 mutations and subset 2 BCR configuration prompts disease progression in IGHV3-21-CLL, whereas cooperation between NOTCH1 mutations, + 12, and subset 8 BCR configuration invariably primes CLL transformation into Richter syndrome. These findings provide a proof of concept that specific stereotyped BCR may promote or select molecular lesions influencing outcome. [ABSTRACT FROM AUTHOR]

The identification of new genetic lesions in chronic lymphocytic leukemia (CLL) prompts a comprehensive and dynamic prognostic algorithm including gene mutations, chromosomal abnormalities, and their changes during clonal evolution. By integrating mutational and cytogenetic analysis in 1274 CLL samples, and by using both a training-validation and a time-dependent design, four CLL subgroups were hierarchically classified: i) high-risk, harboring TP53 and/or BIRC3 abnormalities (10-year survival:29%); ii) intermediate-risk, harboring NOTCH1 and/or SF3B1 mutations and/or del11q22-q23 (10-year survival:37%); iii) low-risk, harboring +12 or a normal genetics (10-year survival:57%); iv) very low-risk, harboring del13q14 only, whose 10-year survival (69.3%) did not significantly differ from a matched general population. This integrated mutational and cytogenetic model independently predicted survival, improved CLL prognostication accuracy compared to FISH karyotype (p<0.0001), and was externally validated in an independent CLL cohort. Clonal evolution from lower to higher risk implicated the emergence of NOTCH1, SF3B1 and BIRC3 abnormalities in addition to TP53 and 11q22-q23 lesions. By taking into account clonal evolution through time-dependent analysis, the genetic model maintained its prognostic relevance at any time from diagnosis. These findings may have relevant implications for the design of clinical trials aimed at assessing the use of mutational profiling to inform therapeutic decisions. [ABSTRACT FROM AUTHOR]

Despite recent therapeutic improvements, the clinical course of diffuse large B-cell lymphoma (DLBCL) still differs considerably among patients. We conducted this retrospective multi-centre study to evaluate the impact of genomic aberrations detected using a high-density genome wide-single nucleotide polymorphism-based array on clinical outcome in a population of DLBCL patients treated with R-CHOP-21 (rituximab, cyclophosphamide, doxorubicine, vincristine and prednisone repeated every 21 d). 166 DNA samples were analysed using the GeneChip Human Mapping 250K NspI. Genomic anomalies were analysed regarding their impact on the clinical course of 124 patients treated with R-CHOP-21. Unsupervised clustering was performed to identify genetically related subgroups of patients with different clinical outcomes. Twenty recurrent genetic lesions showed an impact on the clinical course. Loss of genomic material at 8p23.1 showed the strongest statistical significance and was associated with additional aberrations, such as 17p- and 15q-. Unsupervised clustering identified five DLBCL clusters with distinct genetic profiles, clinical characteristics and outcomes. Genetic features and clusters, associated with a different outcome in patients treated with R-CHOP, have been identified by arrayCGH. [ABSTRACT FROM AUTHOR]

Summary: It was previously shown that the NF-κB pathway is downstream of oncogenic Notch1 in T cell acute lymphoblastic leukemia (T-ALL). Here, we visualize Notch-induced NF-κB activation using both human T-ALL cell lines and animal models. We demonstrate that Hes1, a canonical Notch target and transcriptional repressor, is responsible for sustaining IKK activation in T-ALL. Hes1 exerts its effects by repressing the deubiquitinase CYLD, a negative IKK complex regulator. CYLD expression was found to be significantly suppressed in primary T-ALL. Finally, we demonstrate that IKK inhibition is a promising option for the targeted therapy of T-ALL as specific suppression of IKK expression and function affected both the survival of human T-ALL cells and the maintenance of the disease in vivo. [Copyright &y& Elsevier]

Even in the era of newer and sophisticated prognostic markers, beta2-microglobulin (B2M) remains a simple but very powerful predictor of treatment-free survival (TFS) and overall survival (OS) in patients with chronic lymphocytic leukaemia (CLL). However, B2M levels are heavily influenced by the patient’s glomerular filtration rate (GFR) and this study aimed to evaluate whether GFR-adjusted B2M (GFR-B2M) had improved prognostic value compared to unadjusted B2M in a cohort of over 450 consecutive CLL patients from two separate institutions. Multivariate analysis identified a significantly shorter TFS in patients who were ZAP-70 + ( P < 0·001), with increased GFR-B2M ( P < 0·001), and del(11q) or del(17p) as detected by fluorescence in situ hybridization (FISH; P < 0·001). When OS was evaluated by multivariate analysis, age 65 years or older ( P < 0·001) and poor risk FISH abnormalities ( P < 0·001) had a confirmed adverse prognostic impact, but the predictive value of GFR-B2M was lost in the validation analysis. In all survival models, B2M did not attain independent significance unless GFR-B2M was eliminated from the analysis. In conclusion, GFR-B2M is a better predictor of TFS than unadjusted B2M in CLL patients. [ABSTRACT FROM AUTHOR]

The CEBPA gene codes for a transcription factor that has a pivotal role in controlling proliferation and differentiation of myeloid progenitors. Acquired CEBPA mutations have been found in acute myeloid leukemias (AML) with a good prognosis, and most of these patients have a normal karyotype. In this paper, we report four cases that displayed the same K313dup in the CEBPA gene. All four had an AML-M1 with CD7 positivity and T-cell receptor gamma chain (TCR-γ) rearrangement. This mutation could represent nearly 10% of all CEBPA mutations described to date. K313dup disappeared in samples from patients in complete remission. In transfected cells, the K313dup mutant had reduced protein stability with respect to the wild-type protein. K313dup seems to be selected in leukemic cells, and its frequency in other AML series could be determined using the screening method reported in this paper. [ABSTRACT FROM AUTHOR]

Summary: Epigenetic changes are common alterations in cancer cells. Here, we have investigated the role of Polycomb group proteins in the establishment and maintenance of the aberrant silencing of tumor suppressor genes during transformation induced by the leukemia-associated PML-RARα fusion protein. We show that in leukemic cells knockdown of SUZ12, a key component of Polycomb repressive complex 2 (PRC2), reverts not only histone modification but also induces DNA demethylation of PML-RARα target genes. This results in promoter reactivation and granulocytic differentiation. Importantly, the epigenetic alterations caused by PML-RARα can be reverted by retinoic acid treatment of primary blasts from leukemic patients. Our results demonstrate that the direct targeting of Polycomb group proteins by an oncogene plays a key role during carcinogenesis. [Copyright &y& Elsevier]

In recent years, several attempts have been made to identify novel prognostic markers in patients with intermediate-risk acute myeloid leukemia (IR-AML), to implement risk-adapted strategies. The non-receptor tyrosine kinases are proteins involved in regulation of cell growth, adhesion, migration and apoptosis. They associate with metastatic dissemination in solid tumors and poor prognosis. However, their role in haematological malignancies has been scarcely studied. We hypothesized that PTK2/FAK, PTK2B/PYK2, LYN or SRC could be new prognostic markers in IR-AML. We assessed PTK2, PTK2B, LYN and SRC gene expression in a cohort of 324 patients, adults up to the age of 70, classified in the IR-AML cytogenetic group. Univariate and multivariate analyses showed that PTK2B, LYN and PTK2 gene expression are independent prognostic factors in IR-AML patients. PTK2B and LYN identify a patient subgroup with good prognosis within the cohort with non-favorable FLT3/NPM1 combined mutations. In contrast, PTK2 identifies a patient subgroup with poor prognosis within the worst prognosis cohort who display non-favorable FLT3/NPM1 combined mutations and underexpression of PTK2B or LYN. The combined use of these markers can refine the highly heterogeneous intermediate-risk subgroup of AML patients, and allow the development of risk-adapted post-remission chemotherapy protocols to improve their response to treatment. [ABSTRACT FROM AUTHOR]