scholarly journals Transformation of an Unclassified Myeloproliferative Neoplasm with a RareBCR-JAK2Fusion Transcript Resulting from the Translocation (9;22)(p24;q11)

2015 ◽  
Vol 2015 ◽  
pp. 1-5
Author(s):  
A. N. Chamseddine ◽  
P. Etancelin ◽  
D. Penther ◽  
F. Parmentier ◽  
C. Kuadjovi ◽  
...  
Keyword(s):  
Fusion Gene ◽  
Myeloproliferative Neoplasms ◽  
Present Report ◽  
Myeloproliferative Neoplasm ◽  
Strong Support ◽  
Fusion Transcript ◽  
Derivative Chromosome ◽  
Aggressive Clinical Course

BCR-ABL1negative myeloproliferative neoplasms (MPNs) are known to contain alterations of the tyrosine kinase JAK2 (located on 9p24) that result in constitutive activation of the encoded protein. JAK2 fusions are reported in acute and chronic leukemias of myeloid and lymphoid phenotypes. Here, we report an unclassified case of MPN (MPN-U) showing a t(9;22)(p24;q11), which generates aBCR-JAK2fusion gene by fusing theBCRat intron 13 toJAK2at intron 17 on the derivative chromosome 22. Most reported JAK2 fusions cases reveal an aggressive clinical course and long-term remissions have only been achieved after allogeneic stem cell transplantation (ASCT). To the best of our knowledge, this is the thirteenth case reported worldwide to describe aBCR-JAK2fusion transcript in MPN-U. The present report revealed a sustained complete clinical, hematologic, and cytogenetic remission 35 months after diagnosis and ~24 months after ASCT. RegardingBCR-ABL1  negativeMPN patients this case report provides strong support for a role ofJAK2activation in the oncogenesis and suggests a possible diagnostic and therapeutic target that should be investigated.

scholarly journals A Case of Myeloproliferative Neoplasm with BCR-FGFR1 Rearrangement: Favorable Outcome after Haploidentical Allogeneic Transplantation

2018 ◽  
Vol 2018 ◽  
pp. 1-4 ◽  
Author(s):  
Paola Villafuerte-Gutiérrez ◽  
Montserrat López Rubio ◽  
Pilar Herrera ◽  
Eva Arranz
Keyword(s):  
Kinase Inhibitors ◽  
Fusion Gene ◽  
Myeloproliferative Neoplasms ◽  
Therapeutic Option ◽  
Myeloproliferative Neoplasm ◽  
Allogeneic Transplantation ◽  
Term Survival ◽  
Hematopoietic Stem ◽  
Health Organization

Hematopoietic myeloproliferative neoplasms with FGFR1 rearrangement result in the 8p11 myeloproliferative syndrome that in the current Word Health Organization classification is designated as “myeloid and lymphoid neoplasm with FGFR1 abnormalities.” We report the case of a 66-year-old man who had clinical features that resembled chronic myeloid leukaemia (CML), but bone marrow cytogenetic and fluorescent in situ hybridization (FISH) studies showed t(8;22)(p11;q11) and BCR-FGFR1 fusion gene. He was initially managed with hydroxyurea, and given the aggressive nature of this disease, four months later, the patient underwent an allogeneic hematopoietic stem-cell transplantation (HSCT) from an HLA-haploidentical relative. Currently, HSCT may be the only therapeutic option for long-term survival at least until more efficacious tyrosine kinase inhibitors (TKIs) become available.

Chromosomal Abnormalities in Transformed Ph-Negative Myeloproliferative Neoplasm Are Independent of the JAK2 and the TET2 Statuses.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2900-2900
Author(s):  
Florence Nguyen-Khac ◽  
Lucile Couronne ◽  
Virginie Eclache ◽  
Joris Andrieux ◽  
Eric Lippert ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chromosomal Abnormalities ◽  
Conflicts Of Interest ◽  
Fusion Gene ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
Chronic Phase ◽  
Molecular Data ◽  
Derivative Chromosome ◽  
Phase Duration

Abstract Abstract 2900 Poster Board II-876 Ph-negative myeloproliferative neoplasms: polycythemia vera (PV), essential thrombocythemia (ET) and primitive myelofibrosis (PMF) carry an acquired somatic mutation JAK2V617F in 95% (PV), and in 50 to 60% (ET or PMF) of the patients. Mutations of the TET2 gene have been observed with roughly similar frequencies in the three MPN, irrespective of the presence of JAK2V617F. Evolution to myelofibrosis or acute leukemia may occur with time in MPN patients. Although its molecular bases are poorly understood, the evolution is likely due to the acquisition of additional mutations. To investigate whether cytogenetic abnormalities are distributed differently according to type of transformation and to the JAK2 and TET2 statuses, the Groupe Francophone de Cytogénétique Hématologique has collected 82 patients with transformation of MPN. There were 66 (80%) acute myeloid leukemia or myelodysplastic syndromes (AML/MDS) and 16 (20%) myelofibroses (MF). Of note pipobroman (Pi) treatment seems to be associated with MF, and hydroxyuera (Hu) with AML/MDS evolution in our series. Statistical analyses of clinical, cytogenetic and molecular data are shown Table 1. On the cytogenetical point of view, several points are noteworthy. Some abnormalities were unevenly distributed: there were significantly more -7/del7q and -5/del5q in AML/MDS and tri1q and tri9 in MF. MF and PMF cytogenetic profile looked similar, suggesting a potential link between cytogenetic markers and the phenotype. Although the derivative chromosome der(1;7), observed in 9 patients, is responsible for a loss of 7q, it seemed different from patients with -7/del7q [excluding der(1;7)]. In the -7/del7q group, AML/MDS patients were more numerous than MF patients and the overall survival was shorter compared with the der(1;7) group (22/22 (100%) vs 6/9 (67%) AML/MDS, p=0.02; median: 4 vs 41 months, p=0.0007 respectively). Some specific associations could be observed, such as 17p deletions with 5q deletion (12/30, 40% vs 4/48, 8%, p=0.0007) and 20q deletion with der(1;7) (4/9 (44%) vs11/69 (16%), p=0.03). We detected 24/40 (60%) JAK2V617F and 8/25 (32%) TET2 mutations in transformed MPN, with all possible combinations between the wildtype and mutated forms of both genes. For one post-ET AML patient, JAK2V617F had been observed in a fraction of the granulocytes at the chronic phase. Analysis of blood cDNA obtained at chronic phase showed the same TET2 mutation as observed at acute phase. Because the blast cells were JAK2wt-TET2mut and carried a t(10;16)(q22;q23) affecting the CBFB gene, it is likely that the resulting non-MYH11 CBFB fusion gene transformed a JAK2wt-TET2 mutated progenitor that predominated in the chronic phase. In conclusion, no specific chromosomal abnormality was associated with TET2 or JAK2 mutations. Chromosomal abnormalities were associated with a type of transformation (AML/MDS or MF), suggesting a specific role in the process. In addition, association between some chromosomal abnormalities suggest a specific oncogenic cooperation.Table 1.n=82AML/MDS n=66 MF n=16 p univariate p multivariate Sex F39 (59%)5 (31%)nsnsPV/ET/PMF30/26/1013/3/0nsnsAge at diagnosis of MPN54 [20-82]55.5 [31-69]nsnsChronic Phase (duration, years)12 [2-34]14.5 [3-28]nsnsPrior treatments (n=73*)57*16..No treatment (n=6)60nsnsOne treatment (n=40)33 (58%)7 (44%)nsnsTreatments with Hu (n=57)48 (73%)9 (56%)0.03Treatments with Pi (n=41)26 (46%)15 (93%)0.00060.05Age at transformation66.5[37-92]68 [45-80]nsnsAbnormal karyotype62 (94%)16 (100%)nsnsComplex karyotype45 (68%)7 (44%)nsns-7/del7q28 (42%)3 (18%)0.07ns-7/del7q[without der(1;7)]22 (33%)00.0040.04-5/del5q28 (42%)2 (12%)0.03ns-13/del13q5 (8%)3 (19%)nsns-20/del20q11 (17%)4 (25%)nsns-17/del17p15 (23%)1(6%)nsns+1q14 (22%)9 (56%)0.01ns+95 (8%)4 (25%)0.04ns+811 (17%)3 (19%)nsnsdic17 (26%)3 (19%)nsnsder(1;7)6 (9%)3 (19%)nsnsAmplification MLL0 (0%)nsnsJAK2mut17/31 (55%)7/9 (78%)nsnsTET2mut6/19 (32%)2/6 (33%)nsnsMedian overall survival (months)448<0.00010.001*treatment unknown for 3 patients Disclosures: No relevant conflicts of interest to declare.

Unique Case of Myeloproliferative Neoplasm with Two Rare Clonal Abnormalities: Rare JAK2 Exon 12 Mutation and Rare e14a3 (b3a3) BCR/ABL Fusion Transcript

2018 ◽  
Vol 141 (1) ◽  
pp. 23-27 ◽  
Author(s):  
Mahesh Swaminathan ◽  
Keyur P. Patel ◽  
Julie Huynh-Lu ◽  
Guilin Tang ◽  
Zhuang Zuo ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
Fusion Transcript ◽  
Insertion Mutation ◽  
Unique Case ◽  
Laboratory Features ◽  
Ph Chromosome ◽  
Disease Entities ◽  
Clonal Abnormalities

Myeloproliferative neoplasms (MPNs) are clonal disorders divided into Philadelphia (Ph) chromosome-positive chronic myeloid leukemia (CML) or Ph chromosome-negative MPNs. Co-occurrence of these disease entities is very rare and typically involves presence of common p190 or p210 BCR/ABL fusion transcript (responsible for CML) along with JAK2V617F mutation (most common driver mutation in Ph-negative MPNs). Because of the rarity of such cases, it is not clear if the outcomes are any different in these patients. In this article, we report a unique patient with polycythemia vera driven by a rare complex in-frame deletion-insertion mutation in JAK2 exon 12, and CML driven by uncommon p210 e14a3 (b3a3) BCR/ABL fusion transcript. We describe clinical and laboratory features, bone marrow pathology, treatment, and overall outcome.

scholarly journals THE ROLE OF EARNINGS PERSISTENCE IN VALUATION ACCURACY AND THE TIME HORIZON

2016 ◽  
Vol 56 (1) ◽  
pp. 71-86 ◽  
Author(s):  
RENÊ COPPE PIMENTEL ◽  
ANDSON BRAGA DE AGUIAR
Keyword(s):  
Financial Analysis ◽  
Strong Support ◽  
Earnings Persistence ◽  
Total Risk ◽  
Compensation Contracts ◽  
Listed Firms ◽  
Accounting Numbers ◽  
Short Termism

ABSTRACT Based on the assumption that earnings persistence has implications for both financial analysis and compensation contracts, the aim of this paper is to investigate the role of earnings persistence assuming that (i) more persistent earnings are likely to be a better input to valuation models and (ii) more persistent earnings are likely to serve as a proxy for long-term market and managerial orientation. The analysis is based on Brazilian listed firms from 1995 to 2013, and while we document strong support for the relevance of earnings persistence in financial analysis and valuation, we fail to document a significant relationship between earnings persistence and long-term value orientation. These results are sensitive to different specifications, and additional results suggest that firms' idiosyncratic risk (total risk) is relevant to explain the focus on short-term outcomes (short-termism) across firms. The main contribution of this paper is to offer empirical evidence for the relevance of accounting numbers in both valuation and contractual theories in an emergent market.

Therapeutic Advances in Myeloproliferative Neoplasms: The Role of New-Small Molecule Inhibitors

2012 ◽  
pp. 406-410 ◽  
Author(s):  
Srdan Verstovsek
Keyword(s):  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Myeloproliferative Neoplasms ◽  
Janus Kinase ◽  
Treatment Focus ◽  
Rational Combination ◽  
Short And Long Term ◽  
Jak2 Inhibitors

Overview: The discovery that a somatic point mutation (JAK2V617F) in the Janus kinase 2 ( JAK2) is highly prevalent in patients with myeloproliferative neoplasms (MPNs) has been a crucial breakthrough in our understanding of the underlying molecular mechanisms of these diseases. Therefore, preclinical and clinical research in recent years has focused intensely on the development of new therapies targeted to JAK2. These efforts culminated in recent approval of ruxolitinib as the first official therapy for patients with intermediate- or high-risk myelofibrosis (MF). Therapy with JAK2 inhibitors substantially improves quality of life and reduces organomegaly in MF with or without JAKV617F mutation. Recent results suggest that patients with advanced MF may live longer when receiving therapy with ruxolitinib. However, JAK2 inhibitors do not eliminate the disease and new medications are needed to expand on the benefits seen with JAK2 inhibitors. Although many agents are still in the early stages of development, the wealth of publications and presentations has continued to support our growing understanding of the pathophysiology of MF as well as the potential short- and long-term outcomes of these new and diverse approaches to treatment. Focus of ongoing efforts is particularly on the improvements in anemia and fibrosis, as well as on rational combination trials of JAK2 inhibitors and other potentially active agents. Therapeutic potential and limitations of JAK2 inhibitors and other novel medications in clinical studies are reviewed.

Suppression of MLL-AF4 by Small Interfering RNAs Inhibits Proliferation and Induces Apoptosis in T(4;11)-Positive SEM Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4433-4433
Author(s):  
Johann Greil ◽  
Maria Thomas ◽  
Christian Huenefeld ◽  
Hans-Peter Vornlocher ◽  
Philipp Hadwiger ◽  
...  
Keyword(s):  
Fusion Gene ◽  
Chromosomal Translocation ◽  
Fusion Transcript ◽  
Derivative Chromosome ◽  
Mrna Levels ◽  
Small Interfering Rnas ◽  
Chromosome 11 ◽  
Inhibition Of Proliferation ◽  
Treatment Concepts ◽  
Cell Cycle Transition

Abstract The reciprocal chromosomal translocation t(4;11)(q21;q23) creates the fusion genes MLL-AF4 and AF4-MLL located on derivative chromosome 11 or derivative chromosome 4, respectively. We used small interfering RNAs to suppress the MLL-AF4 fusion gene in the t(4;11)-positive leukaemic cell line SEM. Electroporation of SEM cells with MLL-AF4 siRNAs caused a more than two fold transient decrease in MLL-AF4 mRNA levels, which lasted for three days. The reduction in MLL-AF4 fusion transcript levels were associated with a severely diminished clonogenicity, inhibition of proliferation and of G1-S cell cycle transition and induction of apoptosis. Therefore, MLL-AF4 siRNAs are not only useful to study the functions of MLL-AF4 in leukaemogenesis, but may be also promising agents for novel treatment concepts for t(4;11)-associated leukaemias.

scholarly journals The role of JAK2 inhibitors in MPNs 7 years after approval

Blood ◽  
2018 ◽  
Vol 131 (22) ◽  
pp. 2426-2435 ◽  
Author(s):  
Francesco Passamonti ◽  
Margherita Maffioli
Keyword(s):  
Myeloproliferative Neoplasms ◽  
Symptom Relief ◽  
Primary Myelofibrosis ◽  
Driver Mutations ◽  
Volume Response ◽  
Symptom Response ◽  
Definition Of ◽  
Jak2 Inhibitors

Abstract Myeloproliferative neoplasms (MPNs) include essential thrombocythemia, polycythemia vera (PV), and primary myelofibrosis (MF). Phenotype-driver mutations of JAK2, CALR, and MPL genes are present in MPNs and can be variably combined with additional mutations. Driver mutations entail a constitutive activation of the JAK2/STAT pathway, the key signaling cascade in MPNs. Among JAK2 inhibitors (JAKis), ruxolitinib (RUX) has been approved for the treatment of intermediate and high-risk MF and for PV inadequately controlled by or intolerant of hydroxyurea. Other JAKis, such as fedratinib and pacritinib, proved to be useful in MF. The primary end points in MF trials were spleen volume response (SVR) and symptom response, whereas in PV trials they were hematocrit control with or without spleen response. In advanced MF, RUX achieved a long lasting SVR of >35% in ∼60% of patients, establishing a new benchmark for MF treatment. RUX efficacy in early MF is also remarkable and toxicity is mild. In PV, RUX achieved hematocrit control in ∼60% of cases and SVR in 40%. Symptom relief was evident in both conditions. In the long-term, however, many MF patients lose their SVR. Indeed, the definition of RUX failure and the design of new trials in this setting are unmet needs. Decrease of hemoglobin/platelet levels and increased infection rates are the most common side effects of RUX, and nonmelanoma skin tumors need to be monitored while on treatment. In conclusion, the introduction of JAKis raises the bar of treatment goals in MF and PV.

scholarly journals Methylation Profiling SOCS2 in Philadelphia-Negative Myeloproliferative Neoplasm

2021 ◽  
pp. 452-461
Author(s):  
Elrashed B. Yasin
Keyword(s):  
Cell Lines ◽  
Myeloproliferative Neoplasms ◽  
Methylation Status ◽  
Myeloproliferative Neoplasm ◽  
Accurate Estimate ◽  
Janus Kinase ◽  
Methylation Frequency ◽  
Exon Sequence ◽  
Methylation Profiling

The Janus kinase signal transducer and activator of transcription (JAK / STAT) signalling, which is crucial in Philadelphia-negative myeloproliferative neoplasms’ (MPNs), is negatively regulated by molecules such as SOCS, CISH, and SHP1. SOCS2 methylation has been studied in MPN with conflicting results. Here we examine the methylation status of SOCS2 by specific methylation-specific polymerase chain reaction (MSP) in cell lines and 130 diagnostic prepheral blood samples from Ph-ve MPN. Furthermore, we tried to explain the mismatch of the methylation frequency by assigning the investigated MSP primers to the respective genes. Methylation was detected in normal controls using SOCS2-MSP primers in the 3 'translated exon sequence, but not with primers around the transcription start site in the 5' untranslated regions (5'UTR). SOCS2 was completely unmethylated in primary MPN samples and cell lines. In contrast, SOCS2 methylation when using MSP primers located at the 5'UTR is rare in all studies. In conclusion, SOCS2 methylation is rare in Ph-ve MPN. The appropriate MSP primers are important for an accurate estimate of the methylation frequency. The role of SOCS2 methylation in MPN pathogenesis requires further investigation.

scholarly journals Persistence of the 8;21 translocation in patients with acute myeloid leukemia type M2 in long-term remission

Blood ◽  
1993 ◽  
Vol 82 (3) ◽  
pp. 712-715 ◽  
Author(s):  
G Nucifora ◽  
RA Larson ◽  
JD Rowley
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Fusion Gene ◽  
Fusion Transcript ◽  
Chromosome 8 ◽  
Chromosome 21 ◽  
First Relapse ◽  
Acute Myeloid

The translocation between chromosomes 8 and 21, t(8;21) (q22;q22), is the most frequent abnormality in acute myeloid leukemia (AML) with French-American-British type M2 (FAB-M2) morphology. The breakpoints in this translocation have been characterized at the molecular level, and the genes involved are AML1 on chromosome 21 and ETO on chromosome 8. The rearrangement of the two chromosomes results in a fusion gene and in the production of a consistent fusion transcript on the der(8) chromosome. We have used oligonucleotide primers derived from both sides of the fusion cDNA junction and reverse transcription-polymerase chain reaction (RT-PCR) to analyze six AML-M2 patients with a t(8;21) during various stages of their disease. Two patients studied at diagnosis and one studied at first relapse are alive off therapy and in continuous complete remission for 83 to 94 months. We have detected the AML/ETO fusion transcript in recent peripheral blood samples from each of them. Three other patients also had a fusion transcript detected after 1 to 4 months in remission. Two of these patients subsequently relapsed and died whereas the third patient is alive and in continuous complete remission 70 months later. Thus, our preliminary data suggest that cells with the translocation are still circulating in t(8;21) patients in long-term remission. This finding raises serious questions regarding the interpretation of positive results obtained only with this technique that may not be suitable to decide appropriate further treatment for patients in clinical remission.

scholarly journals Determining the role of inflammation in the selection of JAK2 mutant cells in myeloproliferative neoplasms

2016 ◽  
Author(s):  
Jie Zhang ◽  
Angela Fleischman ◽  
Dominik Wodarz ◽  
Natalia L. Komarova
Keyword(s):  
Myeloproliferative Neoplasms ◽  
Hematologic Malignancy ◽  
Clonal Evolution ◽  
Myeloproliferative Neoplasm ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Evolutionary Advantage ◽  
Functional Forms ◽  
Mutant Cells

AbstractMyeloproliferative neoplasm (MPN) is a hematologic malignancy characterized by the clonal outgrowth of hematopoietic cells with a somatically acquired mutation most commonly in JAK2 (JAK2V 617F). This mutation endows upon myeloid progenitors cytokine independent growth and consequently leads to excessive production of myeloid lineage cells. It has been previously suggested that inflammation may play a role in the clonal evolution of JAK2V 617F mutants. In particular, it is possible that one or more cellular kinetic parameters of hematopoietic stem cells (HSCs) are affected by inflammation, such as division or death rates of cells, and the probability of HSC differentiation. This suggests a mechanism that can steer the outcome of the cellular competition in favor of the mutants, initiating the disease. In this paper we create a number of mathematical evolutionary models, from very abstract to more concrete, that describe cellular competition in the context of inflammation. It is possible to build a model axiomatically, where only very general assumptions are imposed on the modeling components and no arbitrary (and generally unknown) functional forms are used, and still generate a set of testable predictions. In particular, we show that, if HSC death is negligible, the evolutionary advantage of mutant cells can only be conferred by an increase in differentiation probability of HSCs in the presence of inflammation, and if death plays a significant role in the dynamics, an additional mechanism may be an increase of HSC’s division-to-death ratio in the presence of inflammation. Further, we show that in the presence of inflammation, the wild type cell population is predicted to shrink under inflammation (even in the absence of mutants). Finally, it turns out that if only the differentiation probability is affected by the inflammation, then the resulting steady state population of wild type cells will contain a relatively smaller percentage of HSCs under inflammation. If the division-to-death rate is also affected, then the percentage of HSCs under inflammation can either decrease or increase, depending on other parameters.

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