scholarly journals The Genetic Makeup of Myeloproliferative Neoplasms: Role of Germline Variants in Defining Disease Risk, Phenotypic Diversity and Outcome

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2597
Author(s):  
Elena Masselli ◽  
Giulia Pozzi ◽  
Cecilia Carubbi ◽  
Marco Vitale
Keyword(s):  
Disease Risk ◽  
Phenotypic Diversity ◽  
Myeloproliferative Neoplasms ◽  
Hematologic Malignancies ◽  
Response To Therapy ◽  
Germline Variants ◽  
Functional Perspective ◽  
Large Patient ◽  
Malignant State ◽  
Host Genetic

Myeloproliferative neoplasms are hematologic malignancies typified by a substantial heritable component. Germline variants may affect the risk of developing a MPN, as documented by GWAS studies on large patient cohorts. In addition, once the MPN occurred, inherited host genetic factors can be responsible for tuning the disease phenotypic presentation, outcome, and response to therapy. This review covered the polymorphisms that have been variably associated to MPNs, discussing them in the functional perspective of the biological pathways involved. Finally, we reviewed host genetic determinants of clonal hematopoiesis, a pre-malignant state that may anticipate overt hematologic neoplasms including MPNs.

scholarly journals Cytokine Profiling in Myeloproliferative Neoplasms: Overview on Phenotype Correlation, Outcome Prediction, and Role of Genetic Variants

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2136
Author(s):  
Elena Masselli ◽  
Giulia Pozzi ◽  
Giuliana Gobbi ◽  
Stefania Merighi ◽  
Stefania Gessi ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Myeloproliferative Neoplasms ◽  
Expression Patterns ◽  
Hematologic Malignancies ◽  
Molecular Profile ◽  
Chronic Myeloproliferative Neoplasms ◽  
Inflammatory State ◽  
Host Genetic ◽  
Cytokine Profiling

Among hematologic malignancies, the classic Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) are considered a model of inflammation-related cancer development. In this context, the use of immune-modulating agents has recently expanded the MPN therapeutic scenario. Cytokines are key mediators of an auto-amplifying, detrimental cross-talk between the MPN clone and the tumor microenvironment represented by immune, stromal, and endothelial cells. This review focuses on recent advances in cytokine-profiling of MPN patients, analyzing different expression patterns among the three main Philadelphia-negative (Ph-negative) MPNs, as well as correlations with disease molecular profile, phenotype, progression, and outcome. The role of the megakaryocytic clone as the main source of cytokines, particularly in myelofibrosis, is also reviewed. Finally, we report emerging intriguing evidence on the contribution of host genetic variants to the chronic pro-inflammatory state that typifies MPNs.

scholarly journals ASPP2κ Is Expressed In Human Colorectal Carcinoma And Promotes Chemotherapy Resistance And Tumorigenesis

2021 ◽  
Vol 8 ◽  
Author(s):  
Ingmar Rieger ◽  
Vasileia Tsintari ◽  
Mathis Overkamp ◽  
Falko Fend ◽  
Charles D. Lopez ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Chemotherapy Resistance ◽  
Human Tumor ◽  
Exon Skipping ◽  
Predictive Marker ◽  
Hematologic Malignancies ◽  
Response To Therapy ◽  
Dominant Negative ◽  
Gene Products ◽  
Resistance To Therapy

Alternative splicing is a common physiologic mechanism to generate numerous distinct gene products from one gene locus, which can result in unique gene products with differing important functional outcomes depending on cell context. Aberrant alternative splicing is a hallmark of cancer that can contribute to oncogenesis and aggressiveness of the disease as well as resistance to therapy. However, aberrant splicing might also result in novel targets for cancer therapy. ASPP2 is a haplo-insufficient tumor suppressor, that functions through both p53-dependent as well as p53-independent mechanisms to enhance cell death after stress. Interestingly, the common human tumor TP53 mutations result in a loss of the binding sites to ASPP2, leading to impaired induction of apoptosis. Vice versa, attenuation of ASPP2 has been described to be associated with high-risk disease, therapy failure and poor clinical outcome especially in tumors harboring the TP53 wildtype (WT) isoform. We have recently identified a novel, dominant-negative splicing variant of ASPP2, named ASPP2κ, with oncogenic potential. Exon-skipping results in a reading-frame shift with a premature translation stop, omitting most of the ASPP2 C-terminus - which harbors the p53-binding domain. Consequently, the ASPP2-p53 interaction is abrogated, which in part impacts on oncogenesis, aggressiveness of disease and response to therapy. Since ASPP2κ has been shown in hematologic malignancies to promote tumorigenesis, we further wished to determine if aberrant ASPP2κ expression plays a role in human solid tumors. In this report, we find that ASPP2κ is frequently expressed in human colorectal tumors (CRC). Using ASPP2κ overexpressing and interference CRC models, we demonstrate a functional role of ASPP2κ in contributing to oncogenesis and resistance to therapy in CRC by 1) enhancing proliferation, 2) promoting cell migration and, 3) conferring resistance to chemotherapy induced apoptosis. Our findings have far-reaching consequences for future diagnostic and therapeutic strategies for ASPP2κ expressing colorectal cancer patients and provide proof-of-principle to further explore ASPP2κ as potential predictive marker and target for therapy in clinical trials.

Progressive and predictive markers of disease evolution: platelet transcriptome in chronic myeloproliferative neoplasms

2021 ◽  
Author(s):  
Zhu Shen ◽  
Wenfei Du ◽  
Cecelia Perkins ◽  
Lenn Fechter ◽  
Vanita Natu ◽  
...  
Keyword(s):  
Machine Learning ◽  
Risk Stratification ◽  
Disease Risk ◽  
Myeloproliferative Neoplasms ◽  
Penalized Regression ◽  
Machine Learning Algorithms ◽  
Disease Evolution ◽  
Chronic Myeloproliferative Neoplasms ◽  
Age Related ◽  
Wide Range

Predicting disease natural history remains a particularly challenging endeavor in chronic degenerative disorders and cancer, thus limiting early detection, risk stratification, and preventive interventions. Here, profiling the spectrum of chronic myeloproliferative neoplasms (MPNs), as a model, we identify the blood platelet transcriptome as a generalizable strategy for highly sensitive progression biomarkers that also enable prediction via machine learning algorithms. Using RNA sequencing (RNA seq), we derive disease relevant gene expression and alternative splicing in purified platelets from 120 peripheral blood samples constituting two independently collected and mutually validating patient cohorts of the three MPN subtypes: essential thrombocythemia, ET (n=24), polycythemia vera, PV (n=33), and primary or post ET/PV secondary myelofibrosis, MF (n=42), as well as healthy donors (n=21). The MPN platelet transcriptome discriminates each clinical phenotype and reveals an incremental molecular reprogramming that is independent of patient driver mutation status or therapy. Leveraging this dataset, in particular the progressive expression gradient noted across MPN, we develop a machine learning model (Lasso-penalized regression) predictive of the advanced subtype MF at high accuracy (AUC-ROC of 0.95-0.96) with validation under two conditions: i) temporal, with training on the first cohort (n=71) and independent testing on the second (n=49) and ii) 10 fold cross validation on the entire dataset. Lasso-derived signatures offer a robust core set of < 10 MPN progression markers. Mechanistic insights from our data highlight impaired protein homeostasis as a prominent driver of MPN evolution, with persistent integrated stress response. We also identify JAK inhibitor-specific signatures and other interferon, proliferation, and proteostasis associated markers as putative targets for MPN-directed therapy. Our platelet transcriptome snapshot of chronic MPNs establishes a methodological foundation for deciphering disease risk stratification and progression beyond genetic data alone, thus presenting a promising avenue toward potential utility in a wide range of age-related disorders.

Abstract P163: Disparities By Patient Sex? Treatment Duration and Outcomes Of P2Y 12 Inhibitor Therapy in Women Compared to Men After an Acute Myocardial Infarction Among Medicare Beneficiaries

Circulation ◽  
2020 ◽  
Vol 141 (Suppl_1) ◽  
Author(s):  
Ryan P Hickson ◽  
Anna M Kucharska-Newton ◽  
Jo Ellen Rodgers ◽  
Allison E Aiello ◽  
Betsy Sleath ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Disease Risk ◽  
Bleeding Event ◽  
Bleeding Risk ◽  
Response To Therapy ◽  
Inhibitor Therapy ◽  
Risk Scores ◽  
Administrative Claims ◽  
Ischemic Event ◽  
Ischemic Events

Introduction: P2Y 12 inhibitors prevent ischemic events while increasing bleeding risk. It is unclear if clinical differences by sex justify different therapy durations after myocardial infarction (MI). Hypothesis: Women will discontinue P2Y 12 inhibitor therapy earlier than men after MI. Methods: MI hospitalizations in 2008-2013 were identified in a 20% Medicare administrative claims sample. Patients were ≥66 years old; had no recent P2Y 12 inhibitor indication; and had a P2Y 12 inhibitor prescription fill within 30 days post-MI. Therapy duration was measured using days supply and 30-day drug-free interval; duration was modeled as risk of discontinuation over time. Patients were followed up to 24 months. Adjusting for sociodemographics, clinical risks, prescriber characteristics, and contextual factors, disease risk scores (DRSs) were estimated from 4 hazard models predicting P2Y 12 inhibitor discontinuation and 3 competing risks: 1) death or hospice admission, 2) ischemic event (MI, ischemic stroke, revascularization), and 3) bleeding event. Male and female patients were matched 1:1 on the 4 DRSs using Mahalanobis distance. Cause-specific risk differences (RDs) were estimated with the Aalen-Johansen estimator and bootstrapped confidence intervals (CIs). Results: Median time on P2Y 12 inhibitor was 388 days (interquartile range 133-720). Of 30,613 patients (51.2% female), 20,002 were matched. At 24 months, women compared to men had a similar risk of treatment discontinuation (RD 0.84%; 95% CI -0.52, 2.19). While still on a P2Y 12 inhibitor, women were less likely to experience death/hospice admission (RD -0.82%; 95% CI -1.39, -0.24) or ischemic event (RD -0.92%; 95% CI -1.81, 0.06) at 24 months but had a similar bleeding risk (RD -0.07%; 95% CI -0.52, 0.39). Conclusions: Duration of P2Y 12 inhibitor use was similar in men and women. Risks for death/hospice admission and ischemic events while taking a P2Y 12 inhibitor were lower in women, suggesting a differential response to therapy that should be investigated further.

scholarly journals JAK2 (and other genes) be nimble with MPN diagnosis, prognosis, and therapy

Hematology ◽  
2018 ◽  
Vol 2018 (1) ◽  
pp. 110-117 ◽  
Author(s):  
Michele Ciboddo ◽  
Ann Mullally
Keyword(s):  
Clinical Decision Making ◽  
Phenotypic Diversity ◽  
Myeloproliferative Neoplasms ◽  
Clinical Decision ◽  
Prognostic Models ◽  
Driver Mutations ◽  
Therapeutic Approaches ◽  
Ongoing Research ◽  
Substantial Progress ◽  
Made In

Abstract Now that the spectrum of somatic mutations that initiate, propagate, and drive the progression of myeloproliferative neoplasms (MPNs) has largely been defined, recent efforts have focused on integrating this information into clinical decision making. In this regard, the greatest progress has been made in myelofibrosis, in which high-molecular-risk mutations have been identified and incorporated into prognostic models to help guide treatment decisions. In this chapter, we focus on advances in 4 main areas: (1) What are the MPN phenotypic driver mutations? (2) What constitutes high molecular risk in MPN (focusing on ASXL1)? (3) How do we risk-stratify patients with MPN? And (4) What is the significance of molecular genetics for MPN treatment? Although substantial progress has been made, we still have an incomplete understanding of the molecular basis for phenotypic diversity in MPN, and few rationally designed therapeutic approaches to target high-risk mutations are available. Ongoing research efforts in these areas are critical to understanding the biological consequences of genetic heterogeneity in MPN and to improving outcomes for patients.

scholarly journals Liver Fibrosis, Host Genetic and Hepatitis C Virus Related Parameters as Predictive Factors of Response to Therapy against Hepatitis C Virus in HIV/HCV Coinfected Patients

PLoS ONE ◽  
2014 ◽  
Vol 9 (7) ◽  
pp. e101760 ◽  
Author(s):  
Sara Corchado ◽  
Luis F. López-Cortés ◽  
Antonio Rivero-Juárez ◽  
Almudena Torres-Cornejo ◽  
Antonio Rivero ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Liver Fibrosis ◽  
Predictive Factors ◽  
Response To Therapy ◽  
Host Genetic

Ruxolitinib, a Janus Kinase (JAK)-1 and -2 Inhibitor Modulates Microrna (miR) Levels in Patients with Myelofibrosis (MF): miR Levels Might Predict MF Treatment Outcome

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1744-1744
Author(s):  
Taghi Manshouri ◽  
Zeev Estrov ◽  
Liza Knez ◽  
Ying Zhang ◽  
Ross L Levine ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mononuclear Cells ◽  
Myeloproliferative Neoplasms ◽  
Hematologic Malignancies ◽  
Janus Kinase ◽  
Rnase Iii ◽  
Downstream Signaling ◽  
Protein Levels ◽  
Cancer Pathogenesis ◽  
Clinical Benefits

Abstract Abstract 1744 Myeloproliferative neoplasms (MPN) are a class of stem cell–derived hematologic malignancies, characterized by an expansion of one or more myeloid lineages with resulting bone marrow (BM) hypercellularity. A gain-of-function mutation in JAK2, detected in most patients with MPN, induces constitutive activation of JAK2, stimulation of downstream signaling pathways, and activation of several cytokine and growth factor genes. Recent phase I/II clinical trial revealed that ruxolitinib (INCB018424), an oral inhibitor of JAK1 and JAK2, induced marked and durable clinical benefits in patients with primary or secondary MF (Verstovsek S et al. N Engl J Med 12:1117, 2010). Although clinically effective, ruxolitinib induced a modest (13%) suppression of the JAK2V617F allele burden after 12 cycles of therapy and the response did not correlate with the presence of JAK2V617 mutation. Therefore other, yet unknown, mechanisms might be operative in attaining these clinical benefits. Alterations in gene and protein levels affect miRs levels, and miRs have been shown to regulate protein levels, thereby playing a role in cancer pathogenesis (Calin G, et al. PNAS 99:15524, 2002; Merritt MW et al. N Engl J Med 25:2641, 2008; Munker R, et al, Clin Sci 121:141, 2011). Therefore, in MF patients we investigated changes in the levels of RNase III enzymes Dicer and Drosha, which are the two main regulators of miR biogenesis. Deregulation of their expression has been indicative of possible miR alterations in various cancers. We also investigated expression of several miRs (h-miR-16, 21, 29a, 29b1, 29b2, 29c, 155, 181a, and 451). Bone marrow mononuclear cells (MNC) from six best responders in the ruxolitinib study, and MNC from six worst responders were collected (at baseline, one year and two years on therapy), plus six normal control bone marrow MNC, and used for this study. Using qRT-PCR we found that the levels of miR-16, -21, -29 (a, b1, b2, c), -155, -188a and -451 were significantly higher in MF than in normal controls. MiR-155 levels were significantly higher at baseline in best responders than worst responders (P = 0.024). However, after two years of treatment they significantly declined (P = 0.055). The expression of miR-188a was also significantly higher in the worst responders at baseline, as compared to the best responders, but stayed elevated during two years of therapy (P = 0.0021). The levels of RNase III enzymes Dicer and Drosha were significantly lower at baseline in MF MNC as compare to normal MNC. However, after two years of treatment, Dicer level significantly increased in the best responders but not in the worst responders (P = 0.0001). In conclusion, ruxolitinib treatment modulates miR levels and associated enzymes; miR profiling might be useful in predicting response to ruxolitinib. Disclosures: Verstovsek: Incyte Corporation: Research Funding.

Donor Characteristics As Pretransplant Predictive Factors of Long-Term Outcomes After Allogeneic Peripheral Blood Stem Cell Transplantation From HLA-Matched Related and Unrelated Donors in Patients with Hematologic Malignancies

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2000-2000
Author(s):  
Sophie Servais ◽  
Raphaël Porcher ◽  
Marie Robin ◽  
Alienor Xhaard ◽  
Emeline Masson ◽  
...  
Keyword(s):  
Lower Risk ◽  
Disease Risk ◽  
Hematologic Malignancies ◽  
Donor Age ◽  
Long Term Outcomes ◽  
Donor Type ◽  
Recipient Age ◽  
The Impact ◽  
Cmv Status

Abstract Abstract 2000 Background: Over the past 20 years, allogeneic hematopoietic cell transplantation (HCT) has been increasingly performed with peripheral blood stem cells (PB) and gained benefit from better HLA-typing. Similar long-term survival has been suggested after HLA-matched related and unrelated donor HCT. Till now, the optimal strategy for donor selection is still controversial. We evaluated the impact of donor type (10/10 HLA-matched unrelated (MUD) vs. matched related (MRD)) and other donor traits on long term outcomes of patients with hematologic malignancies after PB HCT. Patients and Methods: We analyzed outcomes of 442 consecutive patients with hematologic malignancies who were transplanted with PB either from MUD (n= 164) or MRD (n=278) at our center from 01/2000 to 12/2010. Median patient age was 48 years (range 7–68). Diseases included 122 acute myelogenous leukemias, 62 non-Hodgkin lymphomas, 60 myelodysplastic syndromes, 57 multiple myelomas, 40 acute lymphoblastic leukemias, 37 myeloproliferative disorders, 29 Hodgkin diseases, 20 chronic myeloid leukemias and 15 chronic lymphocytic leukemias. Two-third of patients underwent HCT following reduced intensity conditioning. Graft-versus-host disease (GVHD) prophylaxis consisted mostly in cyclosporine plus MMF or methotrexate. ATG was used in 19% of HCT. We assessed the impact of donor factors (type, age, gender, CMV serologic status and ABO group) on chronic GVHD (cGVHD), relapse, non relapse mortality (NRM) and overall survival (OS). Concerning donor age, as the upper age limit for voluntary PB donation was usually 60 years, we completed our analysis by performing 3 groups according to donor type and age (MUD, MRD<60y and MRD≥60y) and evaluated their influence on outcomes. Donors: Median donor age was 40 years (range 18–72). Most young donors were MUD (<30y: 70%) while older were mainly MRD (≥50y: 98%). Thirty-six patients were transplanted with MRD≥60y. The proportion of female donors was 42% and 113 HCT were performed from female donor to male recipient. Half of patients were transplanted from CMV seronegative donors. Donor/recipient pairs (D/R) were CMV status mismatched in 38% of cases. D/R were ABO matched, minor and major mismatched in 57%, 19% and 24% of cases. Considering donor type, MUD and MRD HCT were balanced for patient age, disease risk and conditioning. MUD received ATG more frequently than MRD (29% MUD vs. 14% MRD [10% MRD<60y and 25% MRD≥60y], P <.0001). Results: The median follow-up (FU) was 36 months (range 2–133) and 25% of patients had a FU of at least 60 months. The cumulative incidence (CIf) of cGVHD at 2 years was 58%. In multivariate analysis, sex mismatch (female > male) increased risk of cGVHD (HR: 1.41 [95% CI 1.05–1.88], P=.02) while MRD≥60y resulted in lower risk (HR: 0.48 [0.25–0.94], P=.031). Donor type by itself did not impact on cGVHD (58% with MRD and 59% with MUD). At 5 years, the CIf of relapse was 34% and was higher with MRD than MUD (39% vs. 24%, P=.038). Adjusted for disease risk, conditioning and infused cells count, only MRD≥60y resulted in significant higher risk of relapse than MUD (HR 2.41[1.26–4.62], P=.008) while MRD <60y had similar risk. The 5 years NRM was 26%. MUD vs. MRD was associated with higher NRM (HR: 1.84 [1.20–2.83], P=.005). Adjusted for recipient age, conditioning, and infused cells count, only MRD<60y were associated with lower risk of NRM than MUD (0.55 [0.35 to 0.86], P=.008) while MRD≥60y had similar NRM. OS was 46% at 5 years and was similar with MUD and MRD. Considering age, MRD≥60y appeared to have notable low OS at 5 years (6%, SE 6%). Adjusted for recipient age, disease risk and infused cells count, HCT from MRD≥60y was associated with higher risk of late (≥18 months) mortality (HR: 4.44 [1.53–12.9], P=.006) than MUD (Fig. 1). Conclusion: Donor/recipient gender parity, donor type and age appeared as significant predictive factors of long term outcomes after HLA-matched PB HCT. Nor donor CMV status nor ABO group seemed to impact on outcomes in our cohort. The selection of a sex mismatched donor (female>male) was associated with significant higher risk of cGVHD. Using PB as graft source, HLA 10/10 MUD provided higher NRM but better disease control and similar OS than MRD. Having combined donor type and age, we observed notable poor outcome (high relapse rate and low OS) for patients transplanted with MRD≥60y in our cohort. Given those results, one may question HCT with old MRD when a younger MUD is available. Disclosures: No relevant conflicts of interest to declare.

Incidence and Outcomes of Myeloproliferative Neoplasms (MPN) in Adolescents and Young Adults (AYAs).

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2845-2845 ◽  
Author(s):  
Naveen Pemmaraju ◽  
Hagop M Kantarjian ◽  
Jorge E. Cortes ◽  
Alfonso Quintas-Cardama ◽  
Sherry A. Pierce ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Systemic Mastocytosis ◽  
Myeloproliferative Neoplasms ◽  
Hypereosinophilic Syndrome ◽  
Hematologic Malignancies ◽  
Kaplan Meier ◽  
Female Predominance ◽  
Significant Difference ◽  
Baseline Characteristics ◽  
Better Than

Abstract Abstract 2845 Background: The MPNs are a family of chronic hematologic malignancies that typically affect pts ages 60–70s. However, there is growing awareness of hematologic malignancies developing in young pts, particularly a unique subset of pts known as AYAs. Little is known about incidence and outcomes of AYA pts with MPNs. Objectives: To determine the incidence and outcomes of MPN AYA pts. Results: We retrospectively reviewed charts of 1,616 MPN pts evaluated at our institution from 1986–2011. A total of 171 MPN pts (11%) were identified whose ages were 16–39, defined as AYA pts (per NCCN guideline recommendations on AYA cancers). Breakdown by MPN subtype: Essential Thrombocytosis, ET (n=78, 46% of AYA MPNs), Polycythemia Vera, PV (n=25, 15%), Myelofibrosis, MF(n=24, 14%), [3 post-ET, 1 post-PV, 20 primary MF], Hypereosinophilic syndrome, HES (n=22, 13%), and Systemic Mastocytosis, SM (n=22, 13%). Baseline characteristics of AYA MPN pts detailed in Table 1. Only significant difference among AYA and non-AYA pts in terms of baseline CBC parameters was WBC: 6.4 (0.4–108.4) in AYA MF vs 10.1 (0.6–361) in non-AYA MF, p=0.0049. Analysis of median overall survival (OS), by Kaplan-Meier method, compared by age group (AYA vs non-AYA pts) and broken down by MPN subtype, shown in Table 2. Conclusion: MPN AYA pts constitute 11% of MPN pts at our institution. Overall, their 5- and 10- yr OS were significantly better than their older counterparts in the 3 major MPN subtypes (ET, PV, MF) and trended towards better survival but not statistically significant in HES and SM. Among AYA MPN pts, female predominance was noted among ET and SM pts and only 1 transformation event was noted among all MPN AYA pts in this analysis. Disclosures: No relevant conflicts of interest to declare.

Multiple Copies of MLL Is The Most Commonly Detected Cytogenetic Abnormality In Newly Diagnosed Multiple Myeloma and May Modify Disease Risk

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1910-1910 ◽  
Author(s):  
Chrystal Landry ◽  
Dory Londono ◽  
Sean M. Devlin ◽  
Alex Lesokhin ◽  
Nikoletta Lendvai ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Overall Survival ◽  
Disease Risk ◽  
Conflicts Of Interest ◽  
Prognostic Significance ◽  
Protein Translation ◽  
Response To Therapy ◽  
Cytogenetic Abnormality ◽  
Newly Diagnosed

Abstract Background Multiple myeloma (MM) is a heterogeneous condition with variable disease course, response to therapy, and survival outcome. Cytogenetics and fluorescent in-situ hybridization (FISH) have identified several recurrent chromosomal aberrations in MM and play important and independent roles in risk stratification (Munshi et al. Blood 2011). However, the pathogenesis of the disorder remains poorly understood. Next-generation sequencing has recently identified that MM involves mutations of genes with roles in protein translation, histone methylation, and blood coagulation (Chapman et al. Nature 2011). Based on the observation that extra copies of MLL, a histone methyltransferase known to regulate the homeotic transcription factor HOXA9 that is highly expressed in MM, is frequently detected in MM, we sought to define the incidence and prognostic significance of excess MLL in MM patients. Methods We identified 188 patients with newly diagnosed MM who had cytogenetics and/or FISH performed on initial, pre-treatment bone marrow specimens at Memorial Sloan-Kettering Cancer Center between January 2009 and December 2012. Standard karyotype and FISH were performed as previously described (Cigudosa et al. Blood 1998, Gerritsen et al. Blood 1992). Probes included LSI IgH/FGF3, LSI IgH/CCND1, LSI IgH/MAF, LSI MLL, LSI p53/cep17, LSI13q14.3/13q34, LSI ETV6, LSI CBFB, LSI 1p36/1q25, and LSI 5,9,15 from Abbott Molecular. Fisher's exact test evaluated the association between MLL and selected abnormalities. Kaplan-Meier methodology estimated overall survival from the date of BM evaluation, and survival was compared using a logrank test. Results In unselected bone marrow specimens, abnormalities were detected by karyotype in 17% (27/156) and FISH in 47% (87/186) of patients tested. Hyperdiploidy, which has been associated with longer survival, was identified in 23% (43/187) of patients, while the unfavorable risk abnormalities, including loss of p53, deletion 13q (by karyotype), translocation (4;14) and excess 1q were seen in 8% (15/179), 8% (12/156), 4% (7/176) and 16% (29/178) of patients, respectively. Translocation (11;14) was seen in 4 patients; translocation (14;16) was not identified in any patient. 28% (51/183) of patients had extra copies of MLL, which was the most frequent genetic abnormality identified. Unexpectedly, this abnormality was significantly associated with both favorable (hyperdiploidy, P = <0.001) and unfavorable (deletion 13q, P = 0.043; excess 1q P = 0.001) risk genetics. While having excess MLL had no impact on the overall survival of standard-risk patients, defined as neither hyperdiploid nor with unfavorable genetics (N = 100), patients with poor-risk genetics (N = 46) and extra copies of MLL had a trend toward better survival, P = 0.06 (Figure 1). Conclusions Karyotype and FISH studies identified excess MLL as the most frequent cytogenetic abnormality in a large cohort of newly diagnosed MM patients. In patients with MM and unfavorable cytogenetics, the presence of excess MLL may ameliorate some of the adverse impact of associated with these abnormalities. Understanding the functional significance of excess MLL, perhaps as it relates to frequently dysregulated HOXA9 in MM, may provide insight into disease pathogenesis and/or identify drugable targets. Disclosures: No relevant conflicts of interest to declare.

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