Lack of Association Between the 46/1 JAK2 Haplotype and the Presence of JAK2V617F Mutation In Splanchnic Vein Thrombosis Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4120-4120
Author(s):  
Eirini G Kouroupi ◽  
Bruno Cassinat ◽  
Aurelie Plessier ◽  
Sylvia Bellucci ◽  
Christine Chomienne ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Jak2v617f Mutation ◽  
Fisher Exact Test ◽  
Peripheral Vein ◽  
Splanchnic Vein Thrombosis ◽  
Vein Thrombosis ◽  
Tag Snp ◽  
Mutational Status ◽  
The Impact

Abstract Abstract 4120 Aim: The majority of myeloproliferative neoplasms (MPN), i.e. Polycythemia vera (PV), Essential Thrombocytemia (ET) and Primary Myelofibrosis, are characterized by the presence of the acquired JAK2V617F gene mutation. Recent studies revealed that the 46/1 or “GGCC” haplotype located in the JAK2 gene is strongly associated with the development of a JAK2V617F positive MPN. However, this particular haplotype was also detected in excess in JAK2V617F negative MPN carrying mutations across JAK2 exon 12 or the MPL gene, suggesting that this germline genetic variation increases the risk of developing a MPN regardless of the acquisition of one particular mutation. A MPN is found in approximately half of the patients presenting with Splanchnic Vein Thrombosis (SVT) and JAK2V617F mutation is present in virtually all of these MPN patients. In this study we sought to clarify the impact of the JAK2 46/1 haplotype on the susceptibility to SVT. Patients and Methods: Peripheral blood was obtained after informed consent; following DNA extraction we proceeded to genotyping using commercially available TaqMan SNP genotyping assays for one tag SNP (rs10974944) which is in complete linkage disequilibrium with the 46/1 haplotype. Results were confirmed using another tag SNP (rs1234867). The study was performed on 170 patients with SVT, 58 patients with peripheral vein thrombosis and 31 patients with JAK2V617F positive PV. Results: In the 170 patients with SVT the frequency of G-allele that stands for the 46/1 haplotype was 0.28 (CC n=89; C/G n=67; G/G n=14), not significantly different from that of the published population controls (n=1500) from the Welcome Trust Case Control Consortium WTCCC (0.24; p=0.11 by the Fisher exact test). The frequency of the 46/1 haplotype in 58 patients with peripheral vein thrombosis was also similar to that of the WTCCC (0.24). However, the frequency of the 46/1 haplotype in SVT patients was significantly different from its frequency in a group of 31 patients with JAK2V617F positive PV (0.52; p=0.0005). When we analysed SVT patients according to their JAK2 mutational status, we found no difference in the frequency of the 46/1 haplotype between the JAK2V617F positive patients (0.27; n=75) and the JAK2V617F negative patients (0.28; n=95) (p=0.90). Of note, a JAK2 allele burden greater than 50% was observed in 11% of patients with JAK2V617F positive SVT and 45% of patients with JAK2V617F positive PV. Conclusions: In this large cohort of 170 patients with SVT the frequency of the 46/1 haplotype was not different from the cohort of controls of the WTCCC. This result suggests that the 46/1 haplotype is not a susceptibility locus for the development of SVT. Moreover, this haplotype was not overrepresented in the group of SVT patients harbouring a JAK2V617F mutation compared to JAK2V617F negative patients. This result is in apparent contradiction with the hypothesis that the 46/1 haplotype predisposes to the acquisition of JAK2V617F mutation or of a MPN, in agreement with recent studies reporting almost identical 46/1 frequencies between V617F-negative patients and V617F-positive patients with low mutation burden (i.e. <50%), which is the case of SVT patients in this series. Disclosures: No relevant conflicts of interest to declare.

scholarly journals JAK2 GGCC (46/1) Haplotype in Unprovoked Venous Thrombotic Events

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4258-4258
Author(s):  
Maged Al-Ammari ◽  
Abdul Ali Peer Zada ◽  
Ibraheem H. Motabi ◽  
Belal M. Albtoosh ◽  
Syed Y. Altaf ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Tertiary Care ◽  
Jak2 V617f ◽  
The Other ◽  
Healthy Population ◽  
Cerebral Vein ◽  
Splanchnic Vein Thrombosis ◽  
Vein Thrombosis

Abstract Background: JAK2 GGCC 46/1 haplotype can be represented by four main SNPs (rs3780367, rs10974944, rs12343867, and rs1159782) which replace one cytosine and three thymidines by two guanosines and two cytosines, generating a "GGCC" combination. These four SNPs located on JAK2 introns 10, 12, 14, and 15, respectively, and are always inherited together, being in complete linkage disequilibrium. The 46/1 component of the name came from Jones et al. study where the haplotype structure of the JAK2 gene was mapped using 14 SNPs genotyped by the Wellcome Trust Case Control Consortium (WTCCC) in 1500 healthy blood donors. Two haplotypes (numbers 46 and 1) were found to be identical except for one SNP, and they have a combined frequency of 0.24 in healthy individuals. Numerous observational studies associate this haplotype with myeloproliferative neoplasms (MPNs), as well as splanchnic vein thrombosis (SVT) and non-splanchnic vein thrombosis (non-SVT). In contrast to 24% frequency noted in healthy population, the frequency goes up to 40-80% in JAK2 V617F mutated MPN, and in 64% of those with JAK2 exon 12 mutations (Anelli et al. IJMS, 2018). We herein report our study of JAK2 GGCC (46/1) Haplotype in unprovoked Venous Thrombotic Events (VTE) in patients with negative thrombophilia workup, including negative JAK2 V617F mutation. Methods: We retrospectively identified patients positive for one of the two SNPs (rs12343867 and rs10974900) and unprovoked venous thrombotic among adult patients with negative thrombophilia workup (including JAK2 mutation) treated at tertiary care center from January 2018 to January 2021. Results: We have identified 8 patients, Table (1), that were positive for JAK2 46/1 haplotype SNPs, of whom 62.5% were homozygous 2/2, 25% heterozygous 1/2, while only 12.5% harbor homozygous 1/1 (a normal variant of JAK2 haplotype). The median age 48.5 years (23-65), and the majority (87.5%) were females. Thrombosis site was noted to be SVT in half of the patients, while non-SVT was noted in the other half (12.5% had cerebral vein thrombosis, 12.5% had deep venous thrombosis, 12.5% had a pulmonary embolism, and 12.5% had jugular vein thrombosis). Half of the patients had more than one site venous thrombosis and the other half had only one site. Around 37.50% of the patients had recurrent venous thrombosis on top of therapeutic anticoagulation. Two patients (25%) had high hemoglobin (17.4/16.7) g/dl, but did not fulfill the criteria for polycythemia vera diagnosis (of whom one is a male smoker and one was a female). None of the patients had leukocytosis or thrombocytosis. By imaging, one patient had mild splenomegaly which could be related to SVT. Conclusion: We report on a potential correlation between unprovoked thrombotic events, mainly venous thrombotic events, with JAK2 46/1 haplotype in patients with a negative thrombophilia workup, a finding that merit further investigation. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals The Zygosity of JAK2V617F Determines the Disease Entities of Myeloproliferative Neoplasms By Modulating Erythropoiesis but Not Megakaryopoiesis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3068-3068
Author(s):  
Hiraku Takei ◽  
Yoko Edahiro ◽  
Lihua Li ◽  
Yoshihisa Mizukami ◽  
Misa Imai ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Clinical Features ◽  
Copy Number ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Philadelphia Chromosome ◽  
Hematopoietic Cell ◽  
Jak2v617f Mutation ◽  
Hematopoietic Stem ◽  
The Impact

Abstract Philadelphia-chromosome negative myeloproliferative neoplasms (MPNs) consists of different clinical entities that include polycythemia vera (PV) and essential thrombocythemia (ET). Despite of differential clinical features, JAK2V617F mutation is found in both PV and ET, leaving the cause of differential biological phenotypes by an oncogene obscure. Previously, studies have shown that higher allele frequencies or expression of JAK2V617F are associated with PV symptom/features in patients or model animals, respectively, suggesting that the copy number of JAK2V617F modulates hematopoietic cell differentiation and thus exhibits differential clinical features. However, this remained elusive in human hematopoiesis. To examine the impact of the zygosity of JAK2V617F allele on hematopoietic differentiation in human cells, we established induced pluripotent stem cells (iPSCs) harboring heterozygous- and homozygous-JAK2V617F mutation using genome-editing techniques from normal iPSCs. The introduction of JAK2V617F mutation with one or two copies did not alter the pluripotency of iPSCs and their capacity to differentiate into hematopoietic stem/progenitor cells (HSPCs) in vitro. When we induced hematopoietic cell differentiation from HSPCs, factor-independent erythropoiesis and megakaryopoiesis were induced in both heterozygous and homozygous JAK2V617F-HSPCs. Furthermore, homozygous JAK2V617F-HSPCs showed higher potential for erythropoiesis compared to the ones with heterozygous JAK2V617F, while the zygosity of JAK2V617F showed less effect on megakaryopoiesis. To further understand the molecular mechanism of hematopoietic cell differentiation modulated by differential copy number of JAK2V617F, we analyzed the activation of JAK-STAT signal by immunoblot analysis. The activation of JAK-STAT signals was more prominent in HSPCs harboring homozygous JAK2V617F, than those with heterozygous JAK2V617F. This suggested that the level of JAK2 phosphorylation was positively correlated with the copy number of JAK2V617F. These observations implied followings: 1) heterozygous JAK2V617F was sufficient to promote the development of MPN by inducing the factor-independent erythropoiesis and megakaryopoiesis; 2) the zygosity of JAK2V617F determined the disease phenotypes of MPNs by modulating erythropoiesis but not megakaryopoiesis; and 3) the homozygous JAK2V617F increased JAK-STAT signaling in HSPCs, promoting an increased erythropoiesis. Disclosures No relevant conflicts of interest to declare.

Evaluating Clonal Dominance in a Murine Knock-in Model of Jak2V617F MPN

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 614-614 ◽  
Author(s):  
Ann Mullally ◽  
Luke Poveromo ◽  
Kristina Brumme ◽  
Fatima Al-Shahrour ◽  
Steven W. Lane ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Progenitor Cell ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Conditional Knockout ◽  
Jak2v617f Mutation ◽  
Loss Of Function ◽  
Hematopoietic Stem ◽  
The Impact

Abstract Abstract 614 Myeloproliferative neoplasms (MPN) are clonal disorders of hematopoiesis but the mechanisms of clonal dominance in these diseases are poorly understood. The JAK2V617F mutation is found in the majority of patients with MPN and is sufficient to confer the MPN phenotype. We recently described a Jak2V617F knock-in MPN model in which the mutation was expressed from the endogenous murine Jak2 promoter and the disease phenotype closely recapitulated human polycythemia vera (PV). In the model we found that the MPN-initiating population is contained within the CD150+CD48− LineagelowSca1+cKithigh(LSK) long-term hematopoietic stem cell (HSC) compartment, and showed that the MPN is cell autonomous and serially transplantable. In long-term competitive transplantation experiments we found that the Jak2V617F CD150+CD48− LSK population demonstrates gradual clonal expansion over time and we are now investigating the regulation of this primitive HSC population in vivo. Erythropoietin (EPO) signaling is reported to be the fundamental defect in polycythemia vera (PV). The JAK2V617F mutation is present in 95% PV patients and can be detected in the HSC compartment. We evaluated the role of EPO signaling in the JAK2V617F mutant HSC compartment using a conditional Jak2V617F knock-in murine model. Floxed Jak2+/VF mice were crossed with Vav Cre or erythropoietin receptor GFP Cre (ErGFPcre) mice resulting in Jak2V617F expression in all hematopoietic lineages or in erythroid restricted Jak2V617F expression respectively. Jak2V617F-ErGFPcre mice demonstrated elevated hematocrit, expanded committed erythroid progenitors and suppressed EPO levels but had an attenuated MPN phenotype as compared with Jak2V617F-Vavcre mice. Notably, the hematopoietic stem and progenitor cell (HSPC) compartment was not expanded in Jak2V617F-ErGFPcre mice and HSCs from both Jak2V617F-Vavcre and Jak2V617F-ErGFPcre mice did not activate phosphoStat5 signaling in response to EPO stimulation. These results indicate that expression of Jak2V617F in the HSC compartment is required for development of a full MPN phenotype and suggest that cytokine receptors other than the EPO receptor are important in mediating clonal dominance within the HSC compartment in JAK2V617F mediated MPN. TET2 is one of three TET gene family members that appear to play a role in DNA demethylation. Acquired TET2 deletions and loss-of-function mutations have been found across a broad spectrum of myeloid malignancies indicating that TET2 may drive a common pathogenic step in myeloid cancers, such as the establishment and/or enhancement of clonal dominance. Tet2 null HSCs have recently been shown to have a competitive repopulating advantage over wild-type HSCs in murine transplantation assays. TET2 loss-of-function mutations are found in approximately 12% of MPN patients, are often found co-mutated with JAK2V617F and have been associated with leukemic transformation of MPN. To evaluate the effects of loss of Tet2 function on the self-renewal and differentiation of Jak2V617F mutant HSCs, we crossed Jak2V617F knock-in mice with Tet2 conditional knockout mice. At 6 weeks of age, Jak2V617F/Tet2 +/− Vav Cre mice do not demonstrate significant differences in MPN phenotype as compared with Jak2V617F/Tet2+/+ Vav Cre mice, in terms of peripheral blood counts, hematopoietic stem and progenitor cell numbers or in colony formation. Additional studies using older mice and Jak2V617F/Tet2−/− Vav Cre animals are underway to further investigate the impact of loss of Tet2 function on Jak2V617F mutant HSCs. Understanding the mechanisms that contribute to clonal dominance in MPN will help facilitate the development of strategies to selectively target MPN stem cells therapeutically, and thereby advance the treatment of MPN patients. Disclosures: No relevant conflicts of interest to declare.

Splanchnic Vein Thrombosis Associated With Myeloproliferative Neoplasms. A Study Of The IWG-MRT In 475 Subjects

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1582-1582 ◽  
Author(s):  
Lisa Pieri ◽  
Paola Guglielmelli ◽  
Massimo Primignani ◽  
Cecilia Brambilla ◽  
Maria Luigia Randi ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Hepatic Failure ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Biological Data ◽  
Budd Chiari Syndrome ◽  
Vein Thrombosis ◽  
Mutational Status ◽  
Chiari Syndrome

Abstract Philadelphia-negative Myeloproliferative Neoplasms (MPN) include Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Myelofibrosis Primary (PMF) and secondary to PV and ET (PPV-, PET-MF); included are also some less characterized entities defined as unclassified MPN (U-MPN). Risk of arterial and venous thrombosis is increased in MPN patients, and thrombosis is one of most important causes of mortality and morbidity. The risk of venous thrombosis in unusual sites, such as splanchnic vessels (SVT), is particularly associated with MPN; SVT can lead to complications such as portal hypertension, esophageal and gastric varices, ascites and hepatic failure. A recent meta-analysis reported that a MPN is the underlying cause of portal vein thrombosis in 31.5% and of Budd Chiari syndrome in 40.9% of cases (Smalberg, 2012). A significant association of SVT with JAK2V617F mutated MPN was reported (Dentali, 2009) but study of other correlations has been hampered by heterogeneity of available patient cohorts comprising relatively small number of cases. We conducted a retrospective multicenter study collecting clinical and biological data of patients (pts) with SVT associated with MPN diagnosed according to WHO2008 criteria, aiming to describe patients’ characteristics, trends and prognostic factors, and their potential implications for clinical practice. Data were collected from 15 international hematology centers in the framework of IWG-MRT. We collected 475 cases of pts with portal, splenic or mesenteric vein thrombosis (75.2%) or Budd Chiari syndrome (24.8%) associated with MPN. In 32% of cases, simultaneous involvement of portal (69.1% of total thrombosis), splenic (30.5%) and mesenteric (25.3%) veins occurred, and in 1.7% they were associated with Budd Chiari syndrome. Frequency of MPN subtype: 38.1% ET (n=181), 34.9% PV (n=166), 16.2% MF (n=77), 10.8% U-MPN (n=51). Median follow-up 87.9 mo (range 0.5-430); female 61.3% (n=292; P<0.0001 vs male); median age at MPN diagnosis (dg) 44.4 y (range 12-90), at SVT dg 44.9 y (range 17-85). In 229 cases (48%) MPN and SVT dg were coincident, while in 104 (22%) SVT occurred before MPN dg (median 40 mo, range 5-335) and in 129 (27%) during MPN follow up (median 79 mo, range 5-394). JAK2V617F mutational status is available for 361 pts: 99% PV, 84.7% ET, 88.1% PMF and 92.9% U-MPN pts were JAK2V617F positive, with a mean allele burden of 56±27.4%, 33.1±25.5%, 39.3±19.4% and 23.8±11.9%, respectively. Erythropoietin-independent colonies (EEC) were present at diagnosis in 80/110 evaluated cases (72.7%), 38/47 PV (84.4%), 32/45 ET (71.1%), 8/11 PMF (72.7%) and 2/7 U-MPN (28.6%). A concurrent thrombophilic state was found in 38.9% of cases. A 12.3% of pts experienced a recurrence of SVT after a median of 29 mo (range 1-378.3) and 35.8% developed thrombosis in other sites (17.7% arterial, 19.3% venous). Esophageal varices were found in 70.6% from which 31.9% bled. MF transformation occurred in 32/166 PV (19%) and in 23/181 ET (13%) pts, with median time to progression of 122.3 mo (range 5.4-377.3) and 125.1 mo (range 39.3-255.3), respectively. Evolution to acute leukemia (AL) occurred in 12 pts (2.7%), of which 2 PMF, 6 PV and 4 ET. In 3 PV and 1 ET pts a PPV and PET-MF transformation occurred before AL. After SVT, 77% of pts received anticoagulation, 23.5% antiaggregant therapy and 1.5% both; 68.8% received cytotoxic drugs, 11.4% of pts were treated with trans jugular porto-systemic shunt. No differences in survival were noted with these approaches. Beta blocker therapy was used in 48.5% of pts and correlated with improved survival (p=0.041) At last follow up 70/473 pts (14.8%) died; causes of death are evolution to AL (16.4%), other cancers (14.5%), disease progression without AL (12.7%), SVT (10.9%), hepatic failure and venous thrombosis other than SVT (9.1% each), heart failure and arterial thrombosis (7.3% each), hemorrhage (5.5%), renal failure and infection (3.6% each). After 10 y follow up 8/166 PV (5%), 14/181 ET (8%), 14/77 PMF (18%) and 1/51 U-MPN (1.96%) pts died (p<0.01). Survival was significantly affected by occurrence of thrombosis other than SVT (p<0.0001) but not recurrence in splanchnic vessels (p=0.068). This large study confirms the strong association between JAK2V617F-mutated MPN and SVT and identifies the category of U-MPN as the prognostically more favorable; thrombosis at sites outside the splanchnic vasculature remains the leading cause of death. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Splanchnic Vein Thrombosis in Acute Pancreatitis and Its Consequences

2021 ◽  
Vol 27 ◽  
pp. 107602962110102
Author(s):  
Łukasz Nawacki ◽  
Jarosław Matykiewicz ◽  
Ewa Stochmal ◽  
Stanisław Głuszek
Keyword(s):  
Acute Pancreatitis ◽  
Severe Disease ◽  
Vascular Complication ◽  
Strong Positive Correlation ◽  
Splanchnic Vein Thrombosis ◽  
Vein Thrombosis ◽  
Computed Tomography Scans ◽  
Negative Effect ◽  
Medical Histories ◽  
The Impact

Splanchnic vein thrombosis (SVT) is a serious vascular complication that can occur in patients with acute pancreatitis. We assessed the incidence of SVT and its relationship with acute pancreatitis (AP) and associated complications. We carried out a retrospective analysis of medical histories from patients hospitalized with AP in a single surgical center. Histories were acquired from patients with abdominal and pelvic computed tomography scans performed between the 2nd and 3rd day of hospitalization. We assessed the impact and extent of thrombosis over the disease course. We found a strong positive correlation (Cramer’s V coefficient = 0.34) between SVT and disease severity. Mortality in the study group was 7.2% (8 patients) of which 5 patients (62.5%) were diagnosed with SVT. We observed an increased incidence of death among patients with thrombosis, with results approaching significance ( P = 0.056). In our study, we found that SVT has a negative effect on the course of AP and is associated with more severe disease and increased mortality.

scholarly journals Outcomes of splanchnic vein thrombosis in patients with myeloproliferative neoplasms in a single center experience

2019 ◽  
Vol 104 (1) ◽  
pp. 72-73 ◽  
Author(s):  
Douglas Tremblay ◽  
Alexander S. Vogel ◽  
Erin Moshier ◽  
Ronald Hoffman ◽  
Marina Kremyanskaya ◽  
...  
Keyword(s):  
Myeloproliferative Neoplasms ◽  
Single Center ◽  
Splanchnic Vein Thrombosis ◽  
Vein Thrombosis ◽  
Single Center Experience

scholarly journals JAK2V617F Mutation in Patient with Splanchnic Vein Thrombosis

2020 ◽  
Vol 36 (4) ◽  
pp. 700-704
Author(s):  
Narender Kumar ◽  
Saniya Sharma ◽  
Jogeshwar Binota ◽  
Jasmina Ahluwalia ◽  
Neelam Varma ◽  
...  
Keyword(s):  
Jak2v617f Mutation ◽  
Splanchnic Vein Thrombosis ◽  
Vein Thrombosis

Extensive Intraclonal Diversification in a Subgroup of Chronic Lymphocytic Leukemia Patients with Stereotyped IGHV4-34/IGKV2-30 B cell Receptors: Implications for Ongoing Interactions with Antigen.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2337-2337
Author(s):  
Lesley-Ann Sutton ◽  
Efterpi Kostareli ◽  
Anastasia Hadzidimitriou ◽  
Nikos Darzentas ◽  
Athanasios Tsaftaris ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Heavy Chain ◽  
Conflicts Of Interest ◽  
Lymphocytic Leukemia ◽  
B Cell Receptors ◽  
Valuable Insight ◽  
Cell Receptors ◽  
Mutational Status ◽  
The Impact

Abstract Abstract 2337 Poster Board II-314 Several studies indicate that the development of chronic lymphocytic leukemia (CLL) may be influenced by antigen (Ag) recognition through the clonotypic B cell receptors (BCRs). However, it is still unclear whether Ag involvement is restricted to the malignant transformation phase or whether the putative Ag(s) may continuously trigger the CLL clone. Valuable insight into these issues may be gleaned from the study of intraclonal diversification (ID) within the immunoglobulin (IG) genes through ongoing somatic hypermutation (SHM). Definitive data regarding ID within IG genes in CLL remains limited and conflicting. In the present study we systematically explored the presence of ID within IG genes of CLL, not only at cohort level but also in subgroups defined by BCR stereotypy and IG gene mutational status. We thus conducted a large-scale subcloning study of both IG heavy and light variable genes, in a total of 1496 and 1008 subcloned sequences from 71 and 56 CLL cases, respectively. The analysis was intentionally biased to cases expressing IGHV4-34/IGKV2-30 IGs (subset #4) and IGHV3-21/IGLV3-21 IGs (subset #2) that exhibit distinctive, subset-biased SHM patterns. PCR reactions were run using the high-fidelity Accuprime Pfx polymerase and at least 14 colonies/case were analyzed. All “non-ubiquitous” sequence changes from the germline were evaluated and recorded as follows: (i) unconfirmed mutation (UCM) - a mutation observed in only one subcloned sequence from the same sample (ii) confirmed mutation (CM) - a mutation observed more than once among subcloned sequences from the same sample. Analysis of heavy chain sequences revealed that 40% (28/71) of cases carried intraclonally diversified IGHV-D-J genes with CMs amongst subclones, whilst 32% (23/71) of cases carried only UCMs. The remaining 28% (20/71) of cases carried sets of identical IGHV-D-J subcloned sequences. Although most cases showed no or low levels of ID, an intense and, likely, functionally driven ID was evident in selected cases, especially those belonging to subset #4. The distinct ID in subset #4 was statistically significant when compared to all other groups defined by IGHV gene usage and mutation status, BCR stereotypy or heavy chain isotype. Subsequent analysis of the clonotypic light chains revealed that the impact of ID was generally low, with the outstanding exception again relating to subset #4. In fact, of 22 IGKV-J rearrangements exhibiting CMs, 11 (50%) utilized the IGKV2-30 gene and notably 10/11 (91%) of these were expressed by subset #4 cases. In such cases, the expressed IGKV2-30 gene was affected by an active and precisely targeted ID, analogous to their partner IGHV4-34 gene. These findings suggest that the SHM mechanism may continuously operate in certain subsets of CLL patients, particularly those cases expressing stereotyped IGHV4-34/IGKV2-30 BCRs typical of subset #4. In such cases, the observed ID patterns attest to the very precise targeting of the SHM process and may be considered as evidence for a “stereotyped response” to an active, ongoing interaction with Ag(s). Disclosures: No relevant conflicts of interest to declare.

Is JAK2 Inducible by Cytotoxic Chemotherapy?

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4979-4979
Author(s):  
Edmond A. Bendaly ◽  
Saud S. Rahman ◽  
Samiah Zafar ◽  
Karen Haglof ◽  
Sherif Ibrahim ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Case Reports ◽  
Lymphoblastic Leukemia ◽  
Myeloproliferative Neoplasm ◽  
Cytotoxic Chemotherapy ◽  
Jak2v617f Mutation ◽  
Platinum Based Chemotherapy ◽  
History Of ◽  
Increased Susceptibility

Abstract Abstract 4979 Introduction The JAK2V617F mutation accounts for most cases of myeloproliferative neoplasms (MPN). Only a few case reports of MPN following cytotoxic chemotherapy have been reported, and all of them were published prior to the discovery of the JAK2V617F mutation. We report a series of 6 patients who developed a JAK2V617F positive MPN following cytotoxic chemotherapy. Patients From 2006 to 2009, 6 patients with a history of a hematologic or an oncologic malignancy who developed an MPN were identified and their medical records retrospectively reviewed. One patient had acute lymphoblastic leukemia, 1 had Hodgkin lymphoma, 1 had squamous cell carcinoma of the head and neck, 1 had cervical cancer, and 2 had breast cancer. All patients were in remission from their primary malignancies at the time the MPN was diagnosed. Five were females. The median age at diagnosis was 72 years. Median time to development of the myeloproliferative neoplasm was 14 years. Type of chemotherapy exposure, MPN diagnosis and time to MPN in each case is shown in the table below. The JAK2V617F mutation was detected either in the peripheral blood or the bone marrow of all patients. There was no predominance of any specific MPN diagnosis. Patients who received platinum-based chemotherapy developed the MPN sooner than those who received alkylators (6 vs 17.5 years respectively). Treatment consisted of phlebotomy, hydroxyurea, anagrelide, aspirin or a combination as deemed appropriate by the treating hematologist. Conclusion These findings lead us to hypothesize whether the development of JAK2V617F positive MPN may be related to prior exposure to cytotoxic chemotherapy. Exposure to platinum-based chemotherapy may cause the disorder to appear sooner compared with exposure to alkylators. Recently, JAK2V617F positive MPN was found to be strongly associated with a specific constitutional haplotype, 46/11 suggesting increased susceptibility to this mutation. Chromosomal analyses are planned to show whether any of the reported patients exhibit this haplotype. Ref: 1.Jones et al, Nat Genet. 2009 Apr;41(4):446-9. 2009 Mar 15. The authors have no relevant disclosure. Disclosures No relevant conflicts of interest to declare.

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