Recurrent Amplified Regions on the Long Arm of Chromosome 1 (1q) Are Associated with Disease Progression In Ph-Negative Myeloproliferative Neoplasms (MPN)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3087-3087
Author(s):  
Vesna Najfeld ◽  
Joseph Tripodi ◽  
Timothy Best ◽  
Mingjiang Xu ◽  
Ronald Hoffman ◽  
...  
Keyword(s):  
High Risk ◽  
Disease Progression ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Snp Array ◽  
Normal Karyotype ◽  
Myelogenous Leukemia ◽  
Chromosome 1 ◽  
Abnormal Karyotype ◽  
Chromosome 1Q

Abstract Abstract 3087 Trisomy of all or part of the long arm of chromosome 1 (1q) is a recurrent abnormality frequently observed at diagnosis in myeloproliferative neoplasms (MPN). Recently, we reported that jumping translocations involving duplications of chromosome 1q (1qJT) represent a clonal marker associated with high risk of transformation to acute myelogenous leukemia (AML) in both MPN and myelodysplastic syndrome (MDS). Breakpoints are often found at either 1q12 or 1q21 (Najfeld et al BJH 2010). Consequently, we hypothesized that these regions are likely to contain a gene or cluster of genes under selection for amplification associated with disease progression. To investigate this, we karyotyped 13 patients (7 males and 6 females) with MPN (primary myelofibrosis [MF]=7, essential thrombocythemia [ET]=2, ET->polycythemia vera- [PV]=1, ET or PV->MF=2, ET->MF->AML=1). Ten of these 13 patients (pts) had an abnormal karyotype, while 3 patients had a normal karyotype. Of pts with an abnormal karyotype, four had trisomy 1q and two had duplication 1q (q12 to q31). The breakpoint 1q12 was observed in 3 pts while the breakpoint 1q21 was identified in 4 pts. One pt had two different populations of cells with a 1q duplication (1q): 36% of cells had a 1q21 breakpoint while 6% cells had a 1q12 breakpoint as identified by FISH using 1q12 and 1q21 specific FISH probes. Additionally, one pt had trisomy for chromosomes 8 and 9, and one had a balanced t(1;9)(p36;p24.1) abnormality. JAK2V617F, an activating mutation implicated in MPN, was present in 6 pts. Of the 13 pts six progressed to AML or had an aggressive disease course that required stem cell transplantation. To map the boundaries of the minimally amplified regions on chromosome 1q associated with disease progression, DNA was isolated from the MPN cells of these 13 patients and genotyped using the Affymetrix Genome-Wide Human SNP Array 6.0. Copy number abnormalities were assessed by Genomic Segmentation (Partek Genomic Suite, St Louis, MO). This analysis revealed seven regions that were recurrently amplified (amplified in at least 4 MPN cases but not in normal controls). Of these regions, three were in 1q21.1 and the rest were telomeric to 1q21. We identified six patients with amplifications in 1q21.1, in contrast to the four identified by karyotype analysis. Of these, one pt had a normal karyotype and was JAK2V617F negative. Intriguingly, the region on 1q21 amplified in this patient was also amplified in the relapse sample of another patient at the time of progression to AML. Of note, this region includes PDE4DIP, which had previously shown to be part of a t(1;5)(q23;q33) translocation in MPN associated with eosinophilia. Of the other recurrent amplifications four pts had a gain of 1q32.1 which includes MDM4, a known regulator of the p53 tumor suppressor. Thus, these data suggest that fine mapping of recurrently amplified regions of chromosome 1q may reveal genes under pressure for amplification in high-risk MPN or that may be involved in the high-risk 1qJT found in both MPN and MDS. Disclosures: No relevant conflicts of interest to declare.

Jumping Translocations of the Long Arms of Chromosome 1 (1qJT) in Myeloproliferative Neoplasms (MPNs) and Myelodysplastic Syndromes (MDS) Are Associated with High Risk of Transformation to Acute Myelogenous Leukemia (AML).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1567-1567
Author(s):  
Vesna Najfeld ◽  
Joseph Tripodi ◽  
Steven Fruchtman ◽  
Lewis R. Silverman ◽  
Richard T. Silver ◽  
...  
Keyword(s):  
High Risk ◽  
Copy Number ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Chromosomal Rearrangements ◽  
Patient Characteristics ◽  
Myelogenous Leukemia ◽  
Chromosome 1 ◽  
Genetic Event

Abstract Abstract 1567 Poster Board I-591 Jumping translocations (JT) are rare cytogenetic events where by a part of one chromosome is translocated to several recipient chromosomes creating multiple related clones within a single patient (pt). Over two-thirds of the already ∼70 reported cases with JTs had multiple myeloma (JR Sawyer et al, 2005). The most frequent donor chromosome involved in JT is the long arm of chromosome 1 (+1q). Although abnormalities of 1q are the 4th most common recurrent rearrangements in both MPN and MDS, 1qJT have been rarely reported in these disorders. Their role in the pathogenesis of MPN and MDS remains unknown. We report a study of 23 pts with myeloid malignancies to determine the role of 1qJT in MPN and MDS. Patient characteristics are shown in Table 1. Of 512 MPN pts (PV=361, PMF=151) cytogenetically evaluated at our institution, we identified 3 pts (PV=2, PMF=1) at diagnosis with 1qJT (0.6% incidence). Additionally 4 of 169 (PV=96, PMF=69) pts with MPN acquired 1qJT during the serial follow up studies over a period of 11 years (the overall incidence was 1.3%, and 4.2% in pts with cytogenetically abnormal karyotypes). Table 1 Characteristics of 23 pts with 1qJT at baseline and sequential studies *One patient had stem cell transplantation The median follow up time was 78 months (mos) and the average time to acquire 1qJT was 58 mos. usually only one or two cells with +1q were initially identified but over time the number of partner chromosomes increased. In 4 pts who acquired 1qJT, this genetic event occurred an average after 5 years while in 1 pt it occurred after 11 years. However, once 1qJT was acquired, 3 of 4 pts developed AML, within an average time of 8 months. The transformation to AML was associated with an increased 1q translocated copy number, suggesting that 1qJT may be a marker of disease progression. By contrast, the incidence of 1qJT at diagnosis of MDS was 0.04% (4 of 1,000). Each of 4 pts, who presented with 1qJTs, had up to three different related clonal populations, all characterized by +1q translocated to 3 different chromosomes. The presence of 1qJT at diagnosis was associated with transformation to AML (3 of 4 pts) after less than 4 mos. Additionally of the 300 pts who were sequentially studied for over a period of 34 mos, 12 pts acquired 1qJT within 27 months (the overall incidence 4%, or 8% among the cytogenetically abnormal). Once 1qJT was acquired, transformation to AML occurred after 8 months (range 0-32) in 10 of 12 pts (83%). This was accompanied with an increased number of JT partner chromosomes. Overall, trisomy 1q, was “jumping” to as many as 11 different chromosomes, creating 11 related clonal populations. All chromosomes except 2, 10 and 12, were recipients of 1qJT, with a greater frequency affecting acrocentric chromosomes (55%). More importantly, 81% of the breakpoints in recipient chromosomes were in the pericentromeric regions. This study represents the largest series of pts with MPN and MDS characterized by 1qJT. The presence of 1qJT at diagnosis or the subsequent acquisition of 1qJT was associated with transformation to AML in 86% of MPN cases and 83% of MDS cases after an average of 8 months. The prognosis of pts with 1qJT tends to be dependent on the translocated 1q copy number: the higher the number of “jumping” 1q being translocated to different partner chromosomes the shorter the time to transformation to AML. These data strongly indicate that 1qJT in MPN and MDS patients represents clonal chromosomal rearrangements associated with a high risk of imminent transformation to AML. Disclosures No relevant conflicts of interest to declare.

A Compendium of Cytogenetic Abnormalities in Myelofibrosis: Molecular and Phenotypic Correlates in 826 Patients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 403-403
Author(s):  
Emnet A Wassie ◽  
Christy Finke ◽  
Naseema Gangat ◽  
Terra L Lasho ◽  
Animesh Pardanani ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
International System ◽  
Normal Karyotype ◽  
Primary Myelofibrosis ◽  
World Health ◽  
Trisomy 8 ◽  
Abnormal Karyotype ◽  
Cytogenetic Abnormalities ◽  
Chromosome 1Q ◽  
Favorable Prognosis

Abstract Background : Recent studies have suggested significant associations between karyotype and certain molecular or phenotypic features in primary myelofibrosis (PMF). In the current study of 835 consecutive patients, we examined the spectrum and prevalence of cytogenetic abnormalities in PMF and their molecular and phenotypic correlates. Methods : PMF diagnosis was according to World Health Organization criteria. Cytogenetic analysis and reporting was done according to the International System for Human Cytogenetic Nomenclature. Statistical analyses considered clinical and laboratory parameters obtained at time of cytogenetic studies. Spectrum and frequency of cytogenetic abnormalities : Analyzable metaphases were obtained in 826 (99%) of 835 patients studied; 681(82%) had ≥20 metaphases analyzed. 352 (42.6%) patients had abnormal karyotype, including 240 (68.2%) sole, 64 (18.2%) two and 48 (13.6%) complex; comparison of these groups revealed lower platelet count (p<0.01), higher DIPSS-plus score (p=0.03) and higher percentage of younger patients (p=0.04) with complex abnormalities. Monosomal karyotype was noted in 20 (5.7%) patients. Approximately 150 individual abnormalities were identified; most frequent were 20q- (23.3%), 13q- (18.2%), +8 (11.1%), +9 (9.9%), duplication of chromosome 1q (9.7%) and -7/7q- (7.1%). Other notable abnormalities including i(17q) (1.4%), 12p- (1.1%) and inv(3) (0.6%) were much less frequent. Trisomy 8 was the most frequent in the context of complex abnormality (25%). Among the 500 patients seen within one year of initial diagnosis, 179 (35.8%) had abnormal karyotype, which included 121 (67.6%) sole, 31 (17.3%) two and 27 (15.1%) complex abnormalities; the most common abnormalities were 20q- (24.6%), 13q- (15.1%), +8 (14%) and +9 (10%) whereas 11q- (1.7%), i(17q) (1.1%), inv(3) (0.6%), and 12p- (0.6%) were infrequent. Molecular correlates : 476 patients were annotated for JAK2, CALR and MPL mutations; abnormal karyotype frequencies were 43% in JAK2, 42% CALR, 33% MPL mutated and 34% triple-negative cases (p=0.3). 13q- was associated with mutant CALR (p=0.03) and +9 with mutant JAK2 (p=0.02). Subsets of patients were also screened for ASXL1, EZH2, IDH, SRSF2, U2AF1, and SF3B1 mutations; in all instances, mutational frequencies were higher in patients with normal karyotype, reaching significance with ASXL1 (p=0.02) and U2AF1 (p=0.01). Mutant SRSF2 was associated with 20q- (p=0.02). Phenotypic correlates : Phenotypic correlates included abnormal karyotype with anemia (p=0.02), leukopenia (p<0.01) and thrombocytopenia (p<0.01); complex karyotype with younger age (p=0.04) and thrombocytopenia (p<0.01); leukopenia with 20q-, +8 and -7/7q-; and thrombocytopenia with 20q- and -7/7q-. Cytopenias were less likely to occur with 13q- (p<0.01), which was instead associated with thrombocytosis (p<0.01). 20q- was associated with lower incidence of marked leukocytosis (p=0.02). Trisomy 8 was associated with lower incidences of constitutional symptoms (p<0.01) and marked splenomegaly (p<0.01). Conclusions : The association of 13q- with CALR mutations in PMF might underlie its association with both thrombocytosis and favorable prognosis. The association of +9 with JAK2 mutations might reflect selective clonal advantage through JAK2V617F dosage enhancement or mutation-induced chromosomal instability. The association of 20q- with mutant SRSF2 and thrombocytopenia warrant further clarification of its reported association with favorable prognosis. Disclosures No relevant conflicts of interest to declare.

Chromosomal and FISH Study of 286 Patients with Primary Myelofibrosis (PMF) Reveals Cryptic Abnormalities and Identifies Lesions Associated with Favorable Prognosis and Disease Progression,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3526-3526
Author(s):  
Vesna Najfeld ◽  
John Mascarenhas ◽  
Steven Fruchtman ◽  
Samuel Cytryn ◽  
Marina Kremyanskaya ◽  
...  
Keyword(s):  
Risk Factor ◽  
Disease Progression ◽  
Myeloproliferative Neoplasms ◽  
Normal Karyotype ◽  
Fusion Partner ◽  
Complex Karyotype ◽  
Wild Type ◽  
Abnormal Karyotype ◽  
Monosomal Karyotype

Abstract Abstract 3526 The pre-treatment karyotype is frequently a potent prognostic determinant of survival in patients (pts) with hematological malignancies. The prognostic significance of chromosomal aberrations, detected at time of diagnosis in pts with essential thrombocythemia (8–10%), polycythemia Vera (PV) (29%) and PMF (approximately 50%), is not well appreciated. We performed a retrospective analysis of 286 pts with PMF who had cytogenetic analyses at our single center between 1984 and July 2011. We first hypothesized that interphase FISH (I-FISH) studies might increase detection of chromosomal rearrangements. Initially, between 2000 and 2008 we performed I-FISH for the detection of the 5 most frequently rearranged loci in Ph negative myeloproliferative neoplasms and extended to 10 loci (1q21, EGR1 at 5q31, D7S511 at 7q31, P15/P16 at 9p21, ATM at 11q22.3, RB1 at 13q14, D20S108 at 20q11 and for numerical detection of chromosomes 7, 8, and 9) as of 2008. The addition of molecular cytogenetics revealed 146 pts (51%) with a normal karyotype and 140 (49%) with abnormal chromosomal lesions, including 12 pts with previously unrecognized lesions. To investigate the relationship between specific chromosomal lesions and JAK2V617F, testing when available after 2007, was performed in 170 of 286 (59%) pts. The V617F mutation was present in 66%. Wild type JAK2 (35%) PMF pts showed del(20q) (4 pts), del(13q) (3 pts), +8 (3 pts, one had cryptic +8), inv(12)(p11q15) (4pts), + der(19)t(1;19) (2pts), complex karyotype (2pts) as well as cryptic lesions (1pt)in a setting of a normal karyotype. The median follow up time of 31pts with normal baseline cytogenetics was 18 months (range 5 to 216 months) and 33% of these patients acquired an abnormal karyotype within the median time of 38mos (range 13–122 months). Four pts acquired a complex karyotype within the mean time of 13 mos (range 11–16 mos) while 2 pts acquired del(20q) within an average of 105 mos (126 and 84 mos). No patient developed a monosomal karyotype. Among 140 pts with an abnormal baseline karyotype, follow up studies were available for 29 pts. The median follow up time was 11 mos (range 5–93 mos) and clonal evolution was observed in 9 pts (31%). The most frequent recurrent abnormalities included del (20)(q11q13) in 30%, del(13q) in 18%, + 8 in 17%, +9/+9p in 16%, trisomy 1q/dup1q in 16%, and i(17q)/del(17p) in 9%. Complex karyotype involving 3 or more chromosomes was identified in 19% while monosomal karyotype, including loss of chromosomes 5, 6,7,17 and18 was observed in 11%. All 6 pts with +der(9)t(1;9)(q21;q12), had PV related PMF and 3 of these pts underwent allogeneic SCT, implying that this abnormality is associated with disease progression. A unique rearrangement, t(1;9) (p36;p24), resulted in identification of a novel JAK2 fusion partner. Survival of these pts based on their cytogenetic risk categories will be presented. Our observations demonstrated that a novel der(19)t(1;19) was detected only in JAK2V617F negative pts, while other abnormalities such as del(20q) and del(13q) are present in both mutation positive and wild type pts. These results confirm previous observations made by us and others that chromosomal abnormalities may occur either before or after JAK2V617F (Wang et al 2009). Even though 33% of pts will progress from a normal to an abnormal karyotype, monosomal karyotype does not appear to be a cytogenetic risk factor in these pts. The observation that the del(20q) abnormality developed over a 7–10 year period in pts with PMF, leads us to conclude that this specific cytogenetic abnormality should be considered a favorable prognostic risk factor. Disclosures: Off Label Use: Oral histone deacetylase inhibitor that targets epigenetic changes in malignant myelofibrosis cells with an goal to modify the disease process.

The Effect of Number of Metaphases Studied and Abnormal Metaphase Percentage On Cytogenetic Risk Stratification in Primary Myelofibrosis

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1742-1742
Author(s):  
Shaina A Rozell ◽  
Biruk Mengistu ◽  
Naseema Gangat ◽  
Curtis A. Hanson ◽  
Ryan A Knudson ◽  
...  
Keyword(s):  
High Risk ◽  
Risk Stratification ◽  
Conflicts Of Interest ◽  
International System ◽  
Normal Karyotype ◽  
Primary Myelofibrosis ◽  
Consecutive Series ◽  
Prognostic Impact ◽  
Abnormal Karyotype ◽  
Very High

Abstract Abstract 1742 Background Karyotype is one of the most potent and reproducible risk factors for both overall (OS) and leukemia-free (LFS) survival in primary myelofibrosis (PMF) (Blood 2011;118:4595). It is currently not clear if the number of metaphases studied or the abnormal metaphase percentage alters this prognostic impact. Methods: An updated Mayo Clinic database of karyotypically- and DIPSS-plus-annotated patients with PMF was used to identify a consecutive series of patients and their cytogenetic information obtained at time of referral was centrally re-reviewed. Cytogenetic results were interpreted and reported according to the International System for Human Cytogenetic Nomenclature; abnormal karyotype was defined by the presence of at least 2 metaphases with structural abnormalities or monosomy or 3 metaphases with polysomy, regardless of number of metaphases examined. For this particular study, the presence of less than 20 evaluable metaphases did not disqualify patients. “Very high risk” karyotype included monosomal karyotype, inv(3) or i(17q) abnormalities (Blood 2011;118:4595). “unfavorable” karyotype included complex or any sole or two abnormalities that included +8, −7/7q-, -5/5q-, inv(3), i(17q), 12p-, or 11q23 rearrangement (Blood 2011;118:4595). All other cytogenetic abnormalities were considered “favorable” Results: A total of 590 patients (median age 65 years; range 19–89 years) including 424 (72%) males. The DIPSS-plus (JCO 2011;29:392) risk distribution was 40% high, 39% intermediate-2, 12% intermediate-1 and 9% low. Cytogenetic findings included 17 (3%) very high risk, 69 (12%) unfavorable, 165 (28%) favorable and 339 (57%) normal karyotypes. The number of bone marrow metaphases studied to report these cytogenetic findings were ≥20 in 468 (79%) patients, 11 to 19 in 71 (12%) patients and ≤10 in 51 (9%) patients; the proportion of cases studied with ≥20 metaphases were 53% for very high risk, 74% for unfavorable, 83% for favorable and 80% for normal karyotype (p=0.006). Among patients with abnormal karyotype, the abnormal metaphase percentage was ≥75% in 148 (59%) patients, 50 to 74% in 36 (15%) patients, 26 to 49% in 27 (11%) patients and ≤25% in 38 (15%) patients; the proportion of patients with ≥75% was 59% for very high risk, 67% for unfavorable and 56% for favorable karyotypes (p=0.70). As expected, OS was significantly different among very high risk, unfavorable, favorable and normal karyotype patients with respective median survivals of 8, 23, 41 and 57 months (p<0.0001). The number of metaphases studied (p=0.62) or the abnormal metaphase percentage (p=0.12), by themselves, did not affect survival. Similarly, the survival difference among the aforementioned cytogenetic risk groups was equally apparent when patients with ≥20 metaphases studied (n=468; P<0.0001) and those with <20 metaphases studied (n=122; p<0.0001) were separately analyzed. Analysis of patients with very high risk or unfavorable karyotype (n=86) revealed no significant effect of abnormal metaphase percentage on survival (Figure; p=0.80). A similar scenario was demonstrated for patients with favorable karyotype (Figure; p=0.24). Conclusions: Neither the number of metaphases examined nor the abnormal metaphase percentage appear to influence the currently recognized cytogenetic risk stratification in PMF. The current study has implications for both clinical practice and clinical research involving cytogenetic prognostication in hematological malignancies. Disclosures: No relevant conflicts of interest to declare.

Genome-Wide Genotype-Based Risk Model for Survival in Acute Myeloid Leukemia Patients with Normal Karyotype.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2526-2526
Author(s):  
Hyeoung-Joon Kim ◽  
Hangseok Choi ◽  
Yeo-Kyeoung Kim ◽  
Sang Kyun Sohn ◽  
Joon Ho Moon ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Risk Model ◽  
Conflicts Of Interest ◽  
Snp Array ◽  
Normal Karyotype ◽  
P Value ◽  
Genome Wide ◽  
Acute Myeloid

Abstract Abstract 2526 Introduction: Single nucleotide polymorphism (SNP) is an inter-individual genetic variation which could explain inter-individual differences of response/survival to chemotherapy. The present study was attempted to build up risk model of survival for acute myeloid leukemia (AML) patients with normal karyotype (AML-NK). Methods and materials: A total of 247 patients with AML-NK was included into the study. Genome-wide SNP array (Affymetrix SNP-array 6.0) was performed in the discovery set (n=118), and genotypes were analyzed for overall survival (OS). After identifying significant SNPs for OS in single SNP analyses, risk model was constructed. Replication was performed in an independent validation cohort (n=129). Results: Out of 632,957 autosomal SNPs meeting genotype data filtration criteria, a total of 82 SNPs were selected and passed into the next step of validation in an independent cohort. In the risk model generation step, finally 4 SNPs (rs2826063, rs12791420, rs11623492 and rs2575369) were meeting stringent criteria for SNP selection as follows: 1) p-value < 0.10 from Cox proportional hazards regression model in adjustment with age and WBC counts at diagnosis; 2) minor allele frequency > 0.05; 3) call rate > 95.0%; 4) high linkage disequilibrium r2 < 0.8. These 4 SNPs were introduced into the risk model, and patients was grouped into 2 groups according to the number of deleterious variables including 4 SNPs and 2 clinical variables (i.e. age and WBC counts at presentation): risk score 0–2 as a low risk (n=80) and 3–6 as a high risk (n=38). The risk model could stratify the patients according to their OS in discovery (p=1.053656•10−4) and in validation set (p=5.38206•10−3). The risk model showed a higher AUC than those being incorporated only clinical or only 4 SNPs, suggesting improved prognostic stratification power of combined model. Conclusion: Genome-wide SNP based risk model obtained from 247 patients with AML-NK can identify high risk group of patients with poor survival using genome wide SNP data. (Clinicaltrials.govIdentifier:NCT01066338) Disclosures: No relevant conflicts of interest to declare.

Long-Term Use of Azacitidine in Private Practice in Brazil: An Analysis of Patients Profiles

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5556-5556
Author(s):  
Renato Centrone ◽  
Laura Yolanda Chialanza Garcia ◽  
Rodrigo Santucci ◽  
Marcelo Bellesso
Keyword(s):  
High Risk ◽  
Conflicts Of Interest ◽  
Performance Status ◽  
Normal Karyotype ◽  
Complete Response ◽  
Myelogenous Leukemia ◽  
Refractory Anemia ◽  
Number Of Patients ◽  
Long Term Treatment

Abstract The AZA-001 study showed that azacitidine has a significant role in prolonging overall survival (OS) in High-Risk Myelodysplastic Syndromes (HR-MDS), particularly in patients with unfavorable cytogenetics, even in the subset of patients without any recorded response except progression. Otherwise, the benefit of azacitidine treatment in OS of HRMDS shows a lack of improvement in survival over the years in most of the patients in a Multicentric Spanish Study Group. Since in our institution we had 34 patients who received Azacitidine for HR-MDS and 20-30% blast Acute Myelogenous Leukemia (AML) during last 36 months, we performed a retrospective analysis of our current long-term treatment patients currently taking Azacitidine, to understand their characteristics. We used WHO classification, IPSS- R score, bone marrow (aspirate) blast count, conventional cytogenetics-based risk, performance status (ECOG) and transfusional dependence. We studied 11 patients with MDS who received at least 06 cycles of Azacitidine,(75 mg/ m2 D1 to D7) until data cut on 1st August 2016. The median age was 71 (range 46-84 years) and 72 % of the patients are male. WHO 2008 classification before beginning of treatment was: 3 AML (2 former RAEB-2 with recent progression), 03 Refractory Anemia with Excess Blasts-2 (RAEB-2), 02 Refractory Anemia with Excess Blasts-1 (RAEB-1), one Refractory Cytopenia with Multilineage Dysplasia (RCMLD) and 02 Refractory Anemia (RA). All but one patient had "good" cytogenetic risk and IPSS-R ranged from 2 to 8,5 (low to high risk), median 4,7 points. Regarding treatment, patients received from 6 to 31 cycles of Azacitidine, with responses according to IWG including one complete response (CR), 03 partial responses (PR), 06 stable diseases (SD) and one Hematological improvement (HI). Transfusion dependence was present at the beginning of treatment in 07 cases, and no change in this parameter happened until those patient's last visit. Performance Status was very good (ECOG=0) in 06 patients before the first dose of azacitidine and good (ECOG-1) in the remaining subjects. At data cut, we had 09 patients with ECOG=0 in the group. This analysis showed that patients had no real improvement of disease parameters since 07 of 11 did not achieve even a partial response, and the same number of patients stay as transfusion-dependents. However, even the worse IPSS-R classified patients had at least a better quality of life and they survived at least one year with treatment. The main finding of this evaluation is that patients who achieve a response other than progression or refractoriness have a good cytogenetic risk, most of them with normal Karyotype, confirming literature. Table Table. Disclosures No relevant conflicts of interest to declare.

Case-Control Study Using Array-Based Genotyping Produced a Panel of Genes Associated with Risk to Acute Myelogenous Leukemia (AML).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2384-2384
Author(s):  
Il-Kwon Lee ◽  
Hee Nam Kim ◽  
Yeo-Kyeoung Kim ◽  
Kyeong-Soo Park ◽  
Deok-Hwan Yang ◽  
...  
Keyword(s):  
Case Control Study ◽  
Snp Array ◽  
Case Control ◽  
Statistical Testing ◽  
Myelogenous Leukemia ◽  
Chromosome 1 ◽  
Repair System ◽  
Haplotype Estimation ◽  
Control Study ◽  
Reduced Risk

Abstract Multiple loci with small genetic effects are thought to be linked to AML pathogenesis. To detect such loci requires systematic screening of large number of single nucleotide polymorphisms (SNPs) within large study population. In this study we tested whether 3104 SNPs in 200 candidate genes were associated with risk to AML. Genes were considered potential candidates for their known or suspected roles in DNA repair system, pharmacogenomics and transcriptional regulation in hematopoiesis or putative pathways related to leukemogenesis. Selection of SNPs was performed using dbSNP and HapMap project databases, with emphasis on non-synonymous SNPs or haplotype tagging SNPs. To discover potential SNPs responsible for AML susceptibility, we conducted a case-control study using Affymetrix targeted genotyping 3K array. We applied this platform to analyze the samples from 309 de novo AML patients and 382 healthy controls. Genotype scorings were processed using GeneChip scanner 3000 TG(Affymetrix) and analyzed with GCOS software(Affymetrix). In total more than 255,000 SNPs were genotyped for this study. Samples with suboptimal call rates were excluded. Statistical testing were carried out using χ2, Cochran-Armitage trend, Fisher’s exact, odds ratio, haplotype estimation, LD block definition. Here we report that 23 SNPs in 16 genes are associated with elevated or reduced risk to AML. Some of associated genes were transcription factors such as ZNF23 and ZNF233. While associated genes were distributed evenly among the whole genome, four associated genes were found on chromosome 1. Among those associated SNPs, two were located in coding region, one in exon-intron boundary, while the rest of SNPs were located in introns of associated genes. Among 23 SNPs identified, two intronic SNPs from 1st intron of BAALC(Brain and acute leukemia, cytoplasmic) gene were associated with the reduced risk to AML. Haplotype estimation and linkage disequilibrium pattern of 9 SNPs including two associated SNPs will be presented. In conclusion, we identified SNPs responsible for AML susceptibility by candidate gene-based SNP array approach. These promising data when supported by further molecular validation would greatly enhance the current understanding of AML predisposition and diseases progression. Implication of polymorphic variants in AML etiopathogenesis will be presented and discussed.

Cytogenetic Evolution (CE) In Patients (pts) with Low and Intermediate Risk Myelodysplastic Syndromes (MDS) Is Associated with Poor Prognosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2941-2941
Author(s):  
Liunan Li ◽  
Elias Jabbour ◽  
Gautam Borthakur ◽  
Stefan Faderl ◽  
Tapan Kadia ◽  
...  
Keyword(s):  
Disease Progression ◽  
Cytogenetic Analysis ◽  
Conflicts Of Interest ◽  
Myelogenous Leukemia ◽  
Intermediate Risk ◽  
Hematopoietic Stem ◽  
Increased Risk ◽  
Significant Difference ◽  
The Impact ◽  
Cytogenetic Evolution

Abstract Abstract 2941 Introduction: MDS is a spectrum of abnormalities in the proliferation and differentiation of hematopoietic stem cells that result in peripheral cytopenias, bone marrow dysplasia and increased risk of transformation to acute myelogenous leukemia (AML). Cytogenetic abnormalities occur in more than 50% of patients (pts) and have an impact on survival and risk of transformation to AML. CE, or acquisition of additional clonal chromosomal abnormalities, has been reported to occur in 30 to 50% of primary MDS pts. Their impact on prognosis and transformation into AML among pts with low and intermediate risk MDS is not known. In this study, we analyzed the impact of CE on prognosis in lower risk MDS. Methods: we reviewed 722 pts clinic records of low and intermediate risk MDS pts at MD Anderson Cancer Center (MDACC) from 2000–2010 and conducted a retrospective analysis of all MDS pts with at least two consecutive cytogenetic analysis (365 patients, 50.6%) and compared the cytogenetic evolution group (CE group) with the group without cytogenetic changes (no CE group). Cytogenetic analysis was performed in the Cytogenetics Laboratory at MDACC. Results: CE was detected in 200 pts (55%). Characteristics of patients with CE are: median age 65 years (23-91), IPSS int-1 79%, diploid CG 42%, excess blasts 25%. Pts with CE were more frequently female (p=0.005), and had more frequently abnormalities of chromosome 5 and 7 (p<0.001) at baseline. There were no statistically significant difference between these two groups (p>0.05) regarding age, WBC, platelet, hgb, ANC, BM blasts percent, diagnosis (RA or RAEB), and IPSS score. There were more chr.-5/-7, insufficient metaphases, and other abnormalities, but less diploid cases in CE group compared with no CE group (p<0.001). History of malignancy (p=0.001) and prior chemotherapy exposure were also associated with CE (p=0.001), but this was not as strong for radiation exposure (p=0.066). Also, more CE patients required therapy for MDS compared to no CE patients (p=0.039). Progression free survival was significantly extended in no CE patients (p=0.02). Overall survival was a longer in no CE (34.1months), compared with CE group (26.2 months), although this was not statistically significant. Conclusion: CE is more commonly observed among pts with high-risk features, and is usually associated with disease progression and resistance. Also, prior malignancy and chemotherapy exposure were associated with CE in this study. This data indicates that genomic instability has a role in disease progression in MDS. Further analysis of CE in MDS is needed. Disclosures: No relevant conflicts of interest to declare.

Disruption of the ASXL1 Gene Is Prevalent In PMF: Analysis of Molecular Genetics and Clinical Phenotypes

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3074-3074
Author(s):  
Brady L Stein ◽  
Donna M Williams ◽  
Michael A McDevitt ◽  
Christine L. O'Keefe ◽  
Ophelia Rogers ◽  
...  
Keyword(s):  
Molecular Genetics ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Single Nucleotide Polymorphism Array ◽  
Myeloproliferative Neoplasms ◽  
Direct Sequencing ◽  
Snp Array ◽  
Uniparental Disomy ◽  
Jak2 V617f ◽  
Wild Type

Abstract Abstract 3074 Background: The myeloproliferative neoplasms, PV, ET and PMF, share phenotypic features and molecular lesions, yet PMF distinguishes itself by its unfavorable natural history and rate of leukemic evolution. These distinctions may occur as a result of cooperating genomic lesions specific to PMF compared to PV or ET. We performed single nucleotide polymorphism array (SNP-A)-based karyotyping in 210 MPN patients and identified 20q11 deletions in 10% of PMF cases and in none of the PV or ET cases. The 20q11 deletion region spanned 1,662 KB and encompassed 37 genes, of which ASXL1 was included. To test whether ASXL1 contained lesions in the MPN cohort at large, we directly sequenced key regions of the ASXL1 gene in 65 PMF, 11 PV and 14 ET cases, as well as 7 controls from the SNP-array cohort. Genomic DNA from neutrophils and in select cases, purified CD34+ cells was used for both SNP-A and direct sequencing. Clinical parameters were correlated with genomic findings and the quantitative JAK2 V617F neutrophil allele burden Molecular genetics: 26/65 (40%) of PMF cases had abnormalities in ASXL1 (4 deletions, 22 mutations) whereas none of the 32 PV, ET or control cases had such lesions. The majority of ASXL1 sequence variations were nonsense lesions including the previously reported 1934dupG which comprised 30% of all of the mutations. The residual ASXL1 allele in all 20q11 deletion cases containing the ASXL1 gene was intact. In three PMF cases, more than one distinct ASXL1 mutation was identified, and cloning experiments on two of those cases indicated that the lesions were biallelic. Using banked samples, we observed the acquisition of an ASXL1 lesion over time, and established that ASXL1 lesions detected in 2 post ET-MF cases were also detected at low levels in the ET phase of the MPN. Genotype/Phenotype Correlations: ASXL1 deletions and mutations were prevalent in de novo PMF (37%), post PV-PMF (20%) post ET-PMF (62%) and in PMF/AML (33%). ASXL1 mutations did not associate with chemotherapy exposure as the prevalence of hydroxyurea use was similar in patients with and without mutations, and ASXL1 –mutation positive cases were present in patients who had never received any form of chemotherapy. There was no dependence upon JAK2 status as the presence of ASXL1 mutations were identified in JAK2 V617F-negative cases (9/26); JAK2 V617F-heterozygous cases (10/26); and JAK2 V617F-homozygous cases (7/26). Based on results of SNP-A, patients with ASXL1 mutations were equally as likely to have uniparental disomy (involving 9p or other regions) and loss/gain abnormalities (>1MB) compared to those without ASXL1 mutations. There were no differences in sex, age, or disease duration between PMF patients with and without ASXL1 mutations. In the ASXL1-mutant group, there was a trend toward a lower median white blood cell count (8 vs. 12.5 k/cu mm; p=0.3) and hemoglobin (9.7 vs. 11 g/dl; p=0.3) compared to ASXL1-wild-type patients. Furthermore, those PMF patients with ASXL1 mutations were significantly more likely to have received anemia-directed therapy (transfusion, erythropoietin, immunomodulating agents, steroids) compared to those without mutations (15/26 (58%) vs. 11/39 (23%); p=0.02). Post ET-MF patients comprised 31% (8/26) of ASXL1-mutant cases, compared to only 10% (4/39) ASXL1- wild-type cases (p=0.03). However, the presence of an ASXL1 mutation did not associate with an accelerated transition rate from ET to MF; among the 12 post ET-MF cases in the cohort, the median time of transition from ET to MF was 15.5 years in those with ASXL1 mutations compared to 7 years in those with ASXL1 wild-type status (p=0.02). Conclusion: Disruption of the ASXL1 gene occurs in 40% of PMF cases. The association of ASXL1 lesions, due to either mutation or deletion, suggests that ASXL1 haplo-insufficiency is associated with a PMF phenotype in the context of other known and unknown lesions, and that disruption of ASXL1 function may directly contribute to the pathophysiology and clinical complications of primary and secondary myelofibrosis. These data support the concepts that cooperative lesions in addition to JAK2 V617F are critical in generating PMF, that PMF is molecularly more complex than either PV or ET, and that the transition of PV or ET to PMF is associated with the acquisition of genomic lesions, such as ASXL1, that are present in PMF at large. Disclosures: No relevant conflicts of interest to declare.

The Ubiquitination-Dependent Interaction of p210 BCR/ABL with β-Catenin Contributes to Chronic Myeloid Leukemogenesis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4186-4186
Author(s):  
Ru Chen ◽  
Mahon Gwen ◽  
Ilona Tala ◽  
Ian Whitehead
Keyword(s):  
Disease Progression ◽  
Kinase Activity ◽  
Conflicts Of Interest ◽  
Consensus Sequence ◽  
Wnt Signaling Pathway ◽  
Myelogenous Leukemia ◽  
Hematopoietic Stem ◽  
Murine Bone Marrow ◽  
Ubiquitin Binding ◽  
Gsk 3Β

Abstract Abstract 4186 Chronic myelogenous leukemia (CML) is a malignant hematopoietic stem cell disorder that is invariably associated with the kinase activity of BCR/ABL. Although the ABL-encoded kinase activity is essential for disease progression, several studies have shown that BCR encoded sequences are also necessary for BCR/ABL-mediated leukemogenesis. In this current study we have identified a ubiquitin binding domain (UBD) in p210 BCR/ABL which is present in all fusion variants of BCR/ABL (p190, p210 and p230). This UBD does not conform to any known consensus sequence, and is unique to BCR and BCR/ABL. Deletion of the UBD does not impair the auto- or trans-kinase activity of p210 BCR/ABL, nor does it impair the interaction between p210 BCR/ABL and GRB2, or the ability of p210 BCR/ABL to activate ERK1/2. A mutation at residue tyr-177 of p210 BCR/ABL also does not impair the interaction with ubiquitin suggesting that the GRB2 and ubiquitin binding sites are adjacent, but separable. β-catenin has been identified as a binding partner for BCR and BCR/ABL, and the docking site has been mapped to a region of BCR/ABL that contains the UBD. Over-expression of p210 BCR/ABL, but not the ubiquitin binding mutant, leads to an accumulation of β-catenin that is phosphorylated on the serine residues that normally trigger ubiquitin-mediated turnover. This difference cannot be attributed to a difference in the activation status of GSK-3β. Treatment with an E1 inhibitor impairs the interaction between β-catenin and p210 BCR/ABL suggesting that the interaction is ubiquitination-dependent. Consistent with this possibility, previous studies have identified a glycine residue in β-catenin that is required for the BCR interaction. Based on these observations we propose a model in which p210 BCR/ABL may influence the Wnt signaling pathway by binding ubiquitinated β-catenin, and stabilizing it against degradation. In a murine bone marrow transplantation model for CML, mice transplanted with hematopoietic cells that express the ubiquitin binding mutant have significantly increased life spans compared to mice transplanted with p210 BCR-ABL expressing cells. This delayed disease progression may be due to a decrease in levels of β-catenin and less granulocyte macrophage progenitors (GMPs), which are thought to function as leukemic stem cells in the blast phase of CML. The role of ubiquitin-mediated b-catenin binding in p210 BCR/ABL-mediated leukemogenesis is currently being explored. Disclosures: No relevant conflicts of interest to declare.

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