Balanced Chromosomal Translocation Research Articles

Proteomic Studies Reveal Disrupted in Schizophrenia 1 as a Player in Both Neurodevelopment and Synaptic Function.

A balanced chromosomal translocation disrupting DISC1 (Disrupted in Schizophrenia 1) gene has been linked to psychiatric diseases, such as major depression, bipolar disorder and schizophrenia. Since the discovery of this translocation, many studies have focused on understating the role of the truncated isoform of DISC1, hypothesizing that the gain of function of this protein could be behind the neurobiology of mental conditions, but not so many studies have focused in the mechanisms impaired due to its loss of function. For that reason, we performed an analysis on the cellular proteome of primary neurons in which DISC1 was knocked down with the goal of identifying relevant pathways directly affected by DISC1 loss of function. Using an unbiased proteomic approach, we found that the expression of 31 proteins related to neurodevelopment (e.g., CRMP-2, stathmin) and synaptic function (e.g., MUNC-18, NCS-1) is altered by DISC1 in primary mouse neurons. Hence, this study reinforces the idea that DISC1 is a unifying regulator of both neurodevelopment and synaptic function, thereby providing a link between these two key anatomical and cellular circuitries.

Time-lapse imaging reveals delayed development of embryos carrying unbalanced chromosomal translocations.

The purpose of the study was to compare the morphokinetic parameters of embryos carrying balanced chromosomal translocations with those carrying unbalanced chromosomal translocations using time-lapse microscopy. The study group included 270 embryos that underwent biopsies on day 3 for preimplantation genetic diagnosis (PGD) for chromosomal translocations in our unit between 2013 and 2015. All embryos were incubated under time-lapse microscopy and evaluated for timing of developmental events up to day 5. The timing of these events was compared between balanced and unbalanced embryos, potentially viable and nonviable variants, and maternal versus paternal inheritance of the translocation. The PGD analysis found that 209 (77%) of the 270 biopsied embryos carried an unbalanced translocation. Embryos carrying unbalanced translocations, which are expected to lead to implantation failure or miscarriage, cleaved less synchronously and were delayed in time of cleavage to the 4-cell stage (t4) and in time of start of blastulation (tSB) compared with balanced embryos (P < 0.05). Furthermore, embryos carrying nonviable translocations demonstrated a significant delay at the time of pronuclei fading (tPNf) compared with those carrying potentially viable translocations (P < 0.05). Embryos whose unbalanced translocations were of maternal origin were significantly delayed in most of the morphokinetic parameters (including tPNf, t2, t3, t4, t6, t7, t8, cc2, s2, and tSB) compared with embryos carrying balanced translocations (P < 0.05). Embryos carrying unbalanced chromosomal translocations mainly of maternal origin undergo delayed development and asynchronous cleavage that may lead to implantation failure or miscarriage.

Integrated Epigenetic Mapping of Human and Mouse Salivary Gene Regulation

Significant effort has been applied to identify the genome-wide gene expression profiles associated with salivary gland development and pathophysiology. However, relatively little is known about the regulators that control salivary gland gene expression. We integrated data from DNase1 digital genomic footprinting, RNA-seq, and gene expression microarrays to comprehensively characterize the cis- and trans-regulatory components controlling gene expression of the healthy submandibular salivary gland. Analysis of 32 human tissues and 87 mouse tissues was performed to identify the highly expressed and tissue-enriched transcription factors driving salivary gland gene expression. Following RNA analysis, protein expression levels and subcellular localization of 39 salivary transcription factors were confirmed by immunohistochemistry. These expression analyses revealed that the salivary gland highly expresses transcription factors associated with endoplasmic reticulum stress, human T-cell lymphotrophic virus 1 expression, and Epstein-Barr virus reactivation. DNase1 digital genomic footprinting to a depth of 333,426,353 reads was performed and utilized to generate a salivary gland gene regulatory network describing the genome-wide chromatin accessibility and transcription factor binding of the salivary gland at a single-nucleotide resolution. Analysis of the DNase1 gene regulatory network identified dense interconnectivity among PLAG1, MYB, and 13 other transcription factors associated with balanced chromosomal translocations and salivary gland tumors. Collectively, these analyses provide a comprehensive atlas of the cis- and trans-regulators of the salivary gland and highlight known aberrantly regulated pathways of diseases affecting the salivary glands.

Mapping of breakpoints in balanced chromosomal translocations by shallow whole-genome sequencing points to EFNA5, BAHD1 and PPP2R5E as novel candidates for genes causing human Mendelian disorders

BackgroundMapping the breakpoints in de novo balanced chromosomal translocations (BCT) in symptomatic individuals provides a unique opportunity to identify in an unbiased way the likely causative genetic defect and thus...

Early molecular response ≤1% has strong prognostic impact for CML patients that switch to second‐line therapy with BCR‐ABL1 ≤10% and no major molecular response

Early molecular response ≤1% has strong prognostic impact for CML patients that switch to second‐line therapy with <i>BCR‐ABL1</i> ≤10% and no major molecular response

Loss of LDAH associated with prostate cancer and hearing loss.

Great strides in gene discovery have been made using a multitude of methods to associate phenotypes with genetic variants, but there still remains a substantial gap between observed symptoms and identified genetic defects. Herein, we use the convergence of various genetic and genomic techniques to investigate the underpinnings of a constellation of phenotypes that include prostate cancer (PCa) and sensorineural hearing loss (SNHL) in a human subject. Through interrogation of the subject's de novo, germline, balanced chromosomal translocation, we first identify a correlation between his disorders and a poorly annotated gene known as lipid droplet associated hydrolase (LDAH). Using data repositories of both germline and somatic variants, we identify convergent genomic evidence that substantiates a correlation between loss of LDAH and PCa. This correlation is validated through both in vitro and in vivo models that show loss of LDAH results in increased risk of PCa and, to a lesser extent, SNHL. By leveraging convergent evidence in emerging genomic data, we hypothesize that loss of LDAH is involved in PCa and other phenotypes observed in support of a genotype-phenotype association in an n-of-one human subject.

Application of karyotype analysis combined with BACs-on-Beads for prenatal diagnosis.

This study explored the clinical application of karyotype analysis combined with BACs-on-Beads (BoBs) technology in prenatal diagnosis. A total of 558 pregnant women who were admitted to Xuzhou Maternity and Child Health Care Hospital from July 2015 to June 2017 were enrolled in this study. All the subjects underwent amniocentesis. BoBs assay was performed for subjects in the observation group, and karyotype analysis was performed for subjects in the control group. The main technical indicators of subjects in the two groups were summarized, and cases of chromosome abnormalities were further evaluated. Clinical follow-up of their pregnancy and neonatal birth was undertaken. Finally, the chromosomal manifestations of these patients were compared with those of normal male and normal female, as well as common chromosomal abnormalities. All 558 pregnant women underwent amniocentesis again. Karyotype analysis combined with BoBs assay of amniotic fluid was performed. Cases of chromosomal abnormalities detected were: 75 cases of trisomy 21, 20 cases of trisomy 18, 1 case of trisomy 13, 27 cases of sex chromosomal abnormalities, 12 cases of balanced chromosome translocation, and 2 cases of chromosome microdeletion. The results indicated that karyotype analysis combined with BoBs technology for prenatal diagnosis was easy to perform, and provided quick results with high accuracy. The two testing methods were complementary to each other, which significantly improved the diagnostic rate of chromosomal abnormalities thus reducing birth defects and guiding continued pregnancy of high-risk pregnant women.

Ewing sarcoma.

Ewing sarcoma is the second most frequent bone tumour of childhood and adolescence that can also arise in soft tissue. Ewing sarcoma is a highly aggressive cancer, with a survival of 70-80% for patients with standard-risk and localized disease and ~30% for those with metastatic disease. Treatment comprises local surgery, radiotherapy and polychemotherapy, which are associated with acute and chronic adverse effects that may compromise quality of life in survivors. Histologically, Ewing sarcomas are composed of small round cells expressing high levels of CD99. Genetically, they are characterized by balanced chromosomal translocations in which a member of the FET gene family is fused with an ETS transcription factor, with the most common fusion being EWSR1-FLI1 (85% of cases). Ewing sarcoma breakpoint region 1 protein (EWSR1)-Friend leukaemia integration 1 transcription factor (FLI1) is a tumour-specific chimeric transcription factor (EWSR1-FLI1) with neomorphic effects that massively rewires the transcriptome. Additionally, EWSR1-FLI1 reprogrammes the epigenome by inducing de novo enhancers at GGAA microsatellites and by altering the state of gene regulatory elements, creating a unique epigenetic signature. Additional mutations at diagnosis are rare and mainly involve STAG2, TP53 and CDKN2A deletions. Emerging studies on the molecular mechanisms of Ewing sarcoma hold promise for improvements in early detection, disease monitoring, lower treatment-related toxicity, overall survival and quality of life.

Abstract 3108: Modeling translocation driven tumors with human induced pluripotent stem cells (hiPSCs) using CRISPR-Cas9: Pseudomyogenic hemangioendothelioma as a proof of principle

Abstract Within the group of vascular tumors balanced chromosomal translocations often drive tumorigenesis. For pseudomyogenic hemangioendothelioma (PHE) no cell line is available, therefore to model this tumor of endothelial origin, we induced a t(7;19)(q22;q13) chromosomal translocation leading to a SERPINE1-FOSB gene fusion in “healthy” human induced Pluripotent Stem Cells (hiPSCs). The hiPSC line was derived using Sendai virus (SeV)-based reprogramming and has been fully characterized. To create a model for PHE we used CRISPR-Cas9 to induce double-stranded breaks in SERPINE1 and FOSB. Using a repair template we introduced a removable neomycin resistance cassette to facilitate selection of cells with translocation. Droplet digital PCR (ddPCR) showed that the wild-type allele of both SERPINE1 and FOSB was mutated in 50% of the cells, and 12% of cells had SERPINE1-FOSB translocations. Screening of single cell-derived clones resulted in 2 clones harboring the correct chromosomal translocation out of 73 screened colonies. Fluorescence in situ hybridization (FISH) using dual-fusion probes confirmed presence of translocation in hiPSCs. Next, isogenic “healthy” and SERPINE1-FOSB targeted hiPSC clones were used to derive endothelial cells (ECs). SERPINE1-FOSB fusion had no effect on differentiation efficiency of ECs from hiPSCs. Fluorescence-activated cell sorting (FACS) confirmed comparable expression of endothelial-specific markers, such as Ve-cadherin, PECAM1, and VEGFR2. Interestingly, expression of CD105 and VEGFR3 that were shown to be elevated in tumor associated endothelial cells were increased in ECs derived from SERPINE1-FOSB targeted hiPSCs compared with ECs derived from “healthy” hiPSCs. Functional assessment of hiPSC-derived ECs showed increased proliferation, tube formation and a decrease in endothelial barrier function in the presence of a SERPINE1-FOSB fusion. Real-time PCR confirmed elevated expression of FOSB (5.9 log2 fold), CD105 (1.9 log2 fold), as well as known pro-angiogenic and pro-inflammatory cytokines, such as VEGF (2.2 log2 fold), IL6 (1.2 log2 fold) and IL8 (2.9 log2 fold). In summary, we demonstrate SERPINE1-FOSB translocation can be introduced into hiPSCs. Importantly, hiPSC-derived ECs that harbor the SERPINE1-FOSB translocation display abnormal tumor endothelium-like phenotype and therefore could serve as an excellent model to study the pathogenesis of PHE. This method could also be potentially interesting to introduce other translocation-driven tumors where no cell lines are available for the discovery of novel targeted therapy and deeper understanding of tumorigenesis. Citation Format: David G. van IJzendoorn, Francijna van den Hil, Karoly Szuhai, Judith V. Bovée, Valeria V. Orlova. Modeling translocation driven tumors with human induced pluripotent stem cells (hiPSCs) using CRISPR-Cas9: Pseudomyogenic hemangioendothelioma as a proof of principle [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3108.

Detection of fetal subchromosomal aberration with cell-free DNA screening led to diagnosis of parental translocation: Review of 11344 consecutive cases in a university hospital

BackgroundFetal chromosome aberrations and sub-chromosomal copy number variations (CNVs) are not rare. There are several ways to detect duplications and deletions; cell-free DNA screening (cfDNA screening) is nowadays an accurate and safe detection method. The objective of this study is to report the feasibility of cfDNA screening as an indicator of parental balanced chromosome translocation. ResultsFrom February 2015 to March 2016, cfDNA screening was offered to 11344 pregnant women. 137 out of 11344 individuals tested positive for aneuploidies using cfDNA screening were confirmed by karyotyping. 6 additional cases also tested positive for other deletion/duplication were confirmed by chromosomal microarray analysis (CMA). 11201 patients tested negative and 10342 of them were confirmed through interviews after delivery. Among the 137 cases that were screened positive in cfDNA screening, 91 were common trisomies (63 cases of trisomy 21, 25 cases of trisomy 18 and 3 cases of trisomy 13) and 46 cases were positive for sex-chromosomal abnormalities. In addition, 6 cases were positive for other deletion/duplication in which 2 were identified as terminal duplication and deletion on different chromosomes. The cfDNA screening findings were confirmed by CMA or karyotyping, and the origins of CNVs were validated afterward by karyotyping or fluorescence in situ hybridization (FISH) using parental blood samples. ConclusionCfDNA screening may help identify deletions and duplications in fetus, which in some cases may indicate risk of a parent being a balanced rearrangement carrier, and that the diagnostic follow-up testing is necessary.

DNA sequence-level analyses reveal potential phenotypic modifiers in a large family with psychiatric disorders

Psychiatric disorders are a group of genetically related diseases with highly polygenic architectures. Genome-wide association analyses have made substantial progress towards understanding the genetic architecture of these disorders. More recently, exome- and whole-genome sequencing of cases and families have identified rare, high penetrant variants that provide direct functional insight. There remains, however, a gap in the heritability explained by these complementary approaches. To understand how multiple genetic variants combine to modify both severity and penetrance of a highly penetrant variant, we sequenced 48 whole genomes from a family with a high loading of psychiatric disorder linked to a balanced chromosomal translocation. The (1;11)(q42;q14.3) translocation directly disrupts three genes: DISC1, DISC2, DISC1FP and has been linked to multiple brain imaging and neurocognitive outcomes in the family. Using DNA sequence-level linkage analysis, functional annotation and population-based association, we identified common and rare variants in GRM5 (minor allele frequency (MAF) > 0.05), PDE4D (MAF > 0.2) and CNTN5 (MAF < 0.01) that may help explain the individual differences in phenotypic expression in the family. We suggest that whole-genome sequencing in large families will improve the understanding of the combined effects of the rare and common sequence variation underlying psychiatric phenotypes.

Familial patellar dislocation associated with t(15;20) (q24;q13.1)

Patellar instability is a common debilitating injury affecting young active individuals. It accounts for approximately 3% of all knee injuries. We report a family, of which five members across three generations, who suffered from autosomal dominant familial recurrent patellar dislocation as well as short stature. All of them have recurrent patellar dislocations before the age of 15. The affected patients in all three generations have been genetically screened. Genotypical evaluation revealed a balanced translocation of chromosomes 15 and 20.

Phenotypic consequences of gene disruption by a balanced de novo translocation involving SLC6A1 and NAA15

Mapping of de novo balanced chromosomal translocations (BCTs) in patients with sporadic poorly characterized disease(s) is an unbiased method of finding candidate gene(s) responsible for the observed symptoms. We present a paediatric patient suffering from epilepsy, developmental delay (DD) and atrial septal defect IIº (ASD) requiring surgery. Karyotyping indicated an apparently balanced de novo reciprocal translocation 46,XX,t(3;4)(p25.3;q31.1), whereas aCGH did not reveal any copy number changes. Using shallow mate-pair whole genome sequencing and direct Sanger sequencing of breakpoint regions we found that translocation disrupted SLC6A1 and NAA15 genes. Our results confirm two previous reports indicating that loss of function of a single allele of SLC6A1 causes epilepsy. In addition, we extend existing evidence that disruption of NAA15 is associated with DD and with congenital heart defects.

Long range haplotyping of paired-homologous chromosomes by single-chromosome sequencing of a single cell

The longest possible haplotype is chromosome haplotype that is a set of co-inherited alleles occurred on a single strand chromosome inherited from one parent. Standard whole-genome shotgun sequencing technologies are limited by the inability to independently study the haplotype of homologous chromosomes due to the short-reads sequencing strategy and disturbance of homologue chromosomes. Here, we investigated several types of chromosomal abnormalities by a dilution-based method to separate an intact copy of homologous chromosome from human metaphase cells, and then single chromosomes were independently amplified by whole-genome amplification methods, converted into barcoded sequencing libraries, and sequenced in multiplexed pools by Illumina sequencers. We analyzed single chromosome derived from single metaphase cells of one patient with balanced chromosomal translocation t(3;5)(q24;q13), one patient with (47, XXY) karyotype and one with (47, XY, 21+) Down syndrome. We determined the translocation region of chromosomes in patient with t(3;5)(q24;q13) balanced chromosomal translocation by shallow whole-genome sequencing, which is helpful to pinpoint the chromosomal break point. We showed that SCS can physically separate and independently sequence three copies of chromosome 21 of Down syndrome patient. SCS has potential applications in personal genomics, single-cell genomics, and clinical diagnosis, particularly in revealing chromosomal level of genetic diseases.

Identification of OAF and PVRL1 as candidate genes for an ocular anomaly characterized by Peters anomaly type 2 and ectopia lentis

Keratolenticular dysgenesis (KLD) and ectopia lentis are congenital eye defects. The aim of this study is the identification of molecular genetic alterations responsible for those ocular anomalies with neurologic impairment in an individual with a de novo balanced chromosome translocation t(11;18)(q23.3;q11.2)dn. Disruption of OAF, the human orthologue of the Drosophila oaf, by the 11q23.3 breakpoint results in reduced expression of this transcriptional regulator. Furthermore, four most likely nonfunctional chimeric transcripts comprising up to OAF exon 3, derived from the der(11) allele, have also been identified. This locus has been implicated by publicly available genome-wide association data in corneal disease and corneal topography. The expression of the poliovirus receptor-related 1(PVRL1) or nectin cell adhesion molecule 1 (NECTIN1), a paralogue of nectin cell adhesion molecule 3 (PVRL3) associated with congenital ocular defects, situated 500 kb upstream from 11q23.3 breakpoint, is increased. The 18q11.2 breakpoint is localized between cutaneous T-cell lymphoma-associated antigen 1(CTAGE1) and retinoblastoma binding protein 8 (RBBP8) genes. Genomic imbalance that could contribute to the observed phenotype was excluded. Analysis of gene expression datasets throughout normal murine ocular lens embryogenesis suggests that OAF expression is significantly enriched in the lens from early stages of development through adulthood, whereas PVRL1 is lens-enriched until E12.5 and then down-regulated. This contrasts with the observation that the proposita's lymphoblastoid cell lines exhibit low OAF and high PVRL1 expression as compared to control, which offers further support that the alterations described above are most likely responsible for the clinical phenotype. Finally, gene interaction topology data for PVRL1 also agree with our proposal that disruption of OAF by the translocation breakpoint and misregulation of PVRL1 due to a position effect contribute to the observed ocular and neurological phenotype.

Reproductive Outcomes in 101 Couples with Balanced Chromosomal Rearrangements

Background: There are very few studies on reproductive outcomes in couples with balanced chromosomal translocations. Findings of such studies can shed light on the possible future outcomes and help in genetic counselling. Objectives: The overall objectives of this study were to report the various chromosomal balanced rearrangements in couples with history of bad reproductive history, to analyse the reproductive outcomes prior to the evaluation and to compare the chromosomal findings with the similar available data from literature. Methods: Reproductive history of couples identified with balanced chromosomal translocations at Genetic Health and Research Centre, Nashik was studied retrospectively, and the various pregnancy outcomes were tabulated and compared with the available literature data. Results: Out of 1580 couples investigated for chromosomal abnormalities for the various indications like recurrent miscarriages, infertility, intrauterine deaths, stillbirths, children with birth defects and neonatal deaths, 101 (6.39%) were found to be carriers of balanced chromosomal rearrangements. A total of 334 pregnancies (average 3.2) were documented in all these carriers. The mean maternal age at the time of evaluation was 29.4 years. Various reproductive outcomes documented were pregnancy losses in 290 couples (2.87 per couple), abnormal births in 25 couples, infertility in 9 couples and normal birth in 19 couples. Conclusion: Karyotyping of couples with bad reproductive outcomes is highly useful for further genetic counselling, appropriate management and close monitoring in subsequent pregnancies. Carriers of balanced chromosomal translocations have better chances of having a normal live birth, however the risk of having the birth of offspring with chromosomal abnormality need to be taken into consideration and prenatal diagnosis offered in all future viable pregnancies.

A Study on Balanced Chromosomal Translocations in Couples with Recurrent Pregnancy Loss.

Background:Recurrent pregnancy loss (RPL) is an obstetric complication that affects couples in their reproductive age. Chromosomal abnormalities, mainly balanced rearrangements, could commonly be present in couples with RPL.Aim:The purpose of this study is to evaluate the contribution of chromosomal abnormalities and balanced reciprocal translocations, in particular occurring in either of the partners, resulting in RPL.Materials and Methods:A retrospective cytogenetic study was carried out on 152 individuals (76 couples) having a history of RPL. The cases were analyzed using G-banding and fluorescence in situ hybridization, wherever necessary.Results:Chromosomal abnormalities were observed in 3.2% of the total RPL cases, of which balanced translocations were observed in 4 (80%) individuals and marker chromosome was detected in 1 (20%) individual. All balanced translocations comprised reciprocal translocations, and no cases of Robertsonian translocations were detected in our study. Among reciprocal translocation carriers, three were male and one was female. Polymorphic variants were noted in 8 (5.3%) individuals.Conclusions:Chromosomal analysis is an important etiological investigation in couples with RPL. Balanced translocations are the most commonly detected chromosomal abnormalities in such couples. Thus, these couples are the best candidates for offering prenatal genetic diagnosis, thereby ensuring a better reproductive outcome.

Clinical Utility of High-Throughput Sequencing for Pregnancies with Ultrasound Anomalies in Southern China

We evaluated the clinical utility of high-throughput sequencing for fetal abnormalities detected with ultrasound examination. This study included pregnant women who were at risk for fetal aneuploidy with or without ultrasonography abnormalities, and who underwent invasive surgery. High-throughput sequencing was used for cell-free fetal DNA analysis, and some positive results were compared with conventional karyotyping. This study involved 971 pregnancies, cell-free fetal DNA identified 15 of 18 (83.33%) as fetal Down syndrome, 4 of 5 (80.00%) as trisomy 18, and 0 of 1 (0.00%) as trisomy 13. Comparing high-throughput sequencing results with conventional fetal karyotypes, we observed that sequencing revealed sub-chromosomal duplications or deletions, but results of karyotyping showed aberrations in chromosome structure or a normal karyotype. One chromosomal balanced translocation was inherited from the mother, another one chromosomal abnormalities was inherited from the father. When fetal chromosomal abnormalities were found by ultrasound abnormalities, non-invasive prenatal testing should not be recommended for the genetic evaluation. Invasive procedure should be first offered to the pregnant woman when abnormal nuchal translucency or other ultrasound abnormalities were found. During invasive prenatal diagnostic testing, fetal chromosomal anomalies should be evaluated by high-throughput sequencing combining with conventional karyotyping.

The Influential Role of BCL2 Family Members in Synovial Sarcomagenesis.

Synovial sarcomas are deadly soft tissue malignancies associated with t(X;18) balanced chromosomal translocations. Expression of the apoptotic regulator BCL2 is prominent in synovial sarcomas and has prompted the hypothesis that synovial sarcomagenesis may depend on it. Herein, it is demonstrated that Bcl2 overexpression enhances synovial sarcomagenesis in an animal model. Furthermore, we determined increased familial clustering of human synovial sarcoma patients with victims of other BCL2-associated malignancies in the Utah Population Database. Conditional genetic disruption of Bcl2 in mice also led to reduced sarcomagenesis. Pharmacologic inhibition specific to BCL2 had no demonstrable efficacy against human synovial sarcoma cell lines or mouse tumors. However, targeting BCLxL in human and mouse synovial sarcoma with the small molecule BH3 domain inhibitor, BXI-72, achieved significant cytoreduction and increased apoptotic signaling. Thus, the contributory role of BCL2 in synovial sarcomagenesis does not appear to render it as a therapeutic target, but mitochondrial antiapoptotic BCL2 family members may be.Implications: The association of BCL2 expression with synovial sarcoma is found to fit with a subtle, but significant, impact of its enhanced presence or absence during early tumorigenesis. However, specific pharmacologic inhibition of BCL2 does not demonstrate a persistent dependence in fully developed tumors. Conversely, inhibition of the BCL2 family member BCLxL resulted in nanomolar potency against human synovial sarcoma cell lines and 50% tumor reduction in a genetically engineered mouse model. Mol Cancer Res; 15(12); 1733-40. ©2017 AACR.

Therapy related-chronic myelomonocytic leukemia (CMML): Molecular, cytogenetic, and clinical distinctions from de novo CMML.

Therapy related myeloid neoplasms (t-MN) including therapy related myelodysplastic syndromes (t-MDS) and acute myeloid leukemia (t-AML) are associated with aggressive disease biologies and poor outcomes. In this large (n = 497) and informative (inclusive of molecular and cytogenetic information) chronic myelomonocytic leukemia (CMML) patient cohort, we demonstrate key biological insights and an independent prognostic impact for t-CMML. T-CMML was diagnosed in 9% of patients and occurred approximately 7 years after exposure to prior chemotherapy and/or radiation therapy. In comparison to de novo CMML, t-CMML patients had higher LDH levels, higher frequency of karyotypic abnormalities and had higher risk cytogenetic stratification. There were no differences in the distribution of gene mutations and unlike t-MDS/AML, balanced chromosomal translocations, abnormalities of chromosome 11q23 (1%) and Tp53 mutations (<2%) were uncommon. Molecularly integrated CMML prognostic models were not effective in risk stratifying t-CMML patients and responses to hypomethylating agents were dismal with no complete responses. Median overall (OS) and leukemia free survival (LFS) was shorter for t-CMML in comparison to d-CMML (Median OS 10.9 vs 26 months and median LFS 50 vs 127 months) and t-CMML independently and adversely impacted OS (P = .0001 HR 2.1 95% CI 1.4-3.0). This prognostic impact was retained in the context of the Mayo Molecular Model (P = .001, HR 2.4, 95% CI 1.5-3.7) and the GFM prognostic model (P < .0001, HR 2.15, 95% CI 1.5-3.7). In summary, we highlight the unique genetics and independent prognostic impact of t-CMML, warranting its inclusion as a separate entity in the classification schema for both CMML and t-MN.