scholarly journals The Role of Nucleophosmin 1 (NPM1) Mutation in the Diagnosis and Management of Myeloid Neoplasms

Life ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 109
Author(s):  
Katalin Kelemen

Nucleophosmin (NPM1) is a multifunctional protein with both proliferative and growth-suppressive roles in the cell. In humans, NPM1 is involved in tumorigenesis via chromosomal translocations, deletions, or mutation. Acute myeloid leukemia (AML) with mutated NPM1, a distinct diagnostic entity by the current WHO Classification of myeloid neoplasm, represents the most common diagnostic subtype in AML and is associated with a favorable prognosis. The persistence of NPM1 mutation in AML at relapse makes this mutation an ideal target for minimal measurable disease (MRD) detection. The clinical implication of this is far-reaching because NPM1-mutated AML is currently classified as being of standard risk, with the best treatment strategy (transplantation versus chemotherapy) yet undefined. Myeloid neoplasms with NPM1 mutations and <20% blasts are characterized by an aggressive clinical course and a rapid progression to AML. The pathological classification of these cases remains controversial. Future studies will determine whether NPM1 gene mutation may be sufficient for diagnosing NPM1-mutated AML independent of the blast count. This review aims to summarize the role of NPM1 in normal cells and in human cancer and discusses its current role in clinical management of AML and related myeloid neoplasms.

2020 ◽  
Vol 21 (23) ◽  
pp. 8975
Author(s):  
Fabio Forghieri ◽  
Vincenzo Nasillo ◽  
Ambra Paolini ◽  
Francesca Bettelli ◽  
Valeria Pioli ◽  
...  

Nucleophosmin (NPM1) gene mutations rarely occur in non-acute myeloid neoplasms (MNs) with <20% blasts. Among nearly 10,000 patients investigated so far, molecular analyses documented NPM1 mutations in around 2% of myelodysplastic syndrome (MDS) cases, mainly belonging to MDS with excess of blasts, and 3% of myelodysplastic/myeloproliferative neoplasm (MDS/MPN) cases, prevalently classified as chronic myelomonocytic leukemia. These uncommon malignancies are associated with an aggressive clinical course, relatively rapid progression to overt acute myeloid leukemia (AML) and poor survival outcomes, raising controversies on their classification as distinct clinico-pathologic entities. Furthermore, fit patients with NPM1-mutated MNs with <20% blasts could benefit most from upfront intensive chemotherapy for AML rather than from moderate intensity MDS-directed therapies, although no firm conclusion can currently be drawn on best therapeutic approaches, due to the limited available data, obtained from small and mainly retrospective series. Caution is also suggested in definitely diagnosing NPM1-mutated MNs with blast count <20%, since NPM1-mutated AML cases frequently present dysplastic features and multilineage bone marrow cells showing abnormal cytoplasmic NPM1 protein delocalization by immunohistochemical staining, therefore belonging to NPM1-mutated clone regardless of blast morphology. Further prospective studies are warranted to definitely assess whether NPM1 mutations may become sufficient to diagnose AML, irrespective of blast percentage.


Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5180-5180
Author(s):  
Chris Ours ◽  
Fiorella Iglesias ◽  
Erin Morales ◽  
Luke Maese ◽  
Archana M Agarwal ◽  
...  

Abstract Introduction: Patients with Down syndrome (DS) have an increased risk of hematological disorders, including transient abnormal myelopoiesis (TAM), acute lymphoblastic leukemia (ALL), myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Twenty percent of patients with TAM subsequently develop myeloid neoplasm in the first 4 years of life. MDS represents a clonal aberration thought to be a pre-leukemic condition characterized clinically by cytopenias and erythroid, myeloid and/or megakaryocytic dysplasia in the bone marrow with or without increase in blasts and harbors a concordant, clone-specific mutation of GATA1. WHO 2016 classification of hematopoietic neoplasms does not distinguish between MDS and AML, as their overall prognosis appears to be similar. However, due to the rarity of this disorder, limited clinical and laboratory data is available, contributing to difficulties in establishing the diagnosis. Here we describe our center's recent experience with the diagnosis and molecular findings of myeloid neoplasm associated with Down syndrome (MN-DS). Design/Method: Retrospective review of the patient's electronic medical record and review of the literature was conducted. Routine karyotype, fluorescent in-situ hybridization (FISH) and next generation sequencing (NGS) studies were reviewed where available. Results: Six patients with DS diagnosed with AML or MDS were identified over a 3-year period. Mean age of the cohort was 18.5 (range 12-24) months with a slight female predominance. Three patients had a history of TAM, all of which resolved without intervention. Three patients had asymptomatic thrombocytopenia after birth without blasts or GATA1 mutation confirmation. One of the three patients with a history of TAM presented with overt AML, while in the others diagnosis was challenging. By WHO 2008 classification of myeloid neoplasms, four patients had refractory anemia with excess blasts, one had refractory cytopenia with multilineage dysplasia, and one had AML. For two patients, in whom myeloid directed next generation sequencing was obtained, mutations were found in GATA1, EZH2, and NRAS. One of the patients in our series presented with AML with gain of MECOM, RPN1 loss and D5S23 deletion by FISH and succumbed to relapsed disease. All patients were treated per Children's Oncology Group AAML1531 arm A protocol that included 3 induction cycles and 2 intensification cycles, except for a single patient that received one cycle per AAML0431 and completed therapy per AAML1531 arm B high risk due to persistent disease following initial induction cycle. Two patients are currently receiving treatment, three have no evidence of disease recurrence on follow up ranging from 2 to 18 months, and one of the patients has died due to relapsed/refractory disease. Conclusions: We present six cases of MN-DS in patients less than four years of age. Our cohort is representative of the diversity encountered in this rare disease including patients with 1) isolated cytopenia in the absence of overt morphological findings, 2) myelodysplasia, and 3) AML. In our patient with overt AML there were karyotypic features such as gain of MECOM, which with specific translocation partners has previously been described to portend a poor prognosis. This and other cytogenetic features perhaps warrant further investigation given our patient's refractory disease. In the patient with refractory cytopenia without blasts, there was a subpopulation of cells identified by NGS panel showing mutations in GATA1, EZH2, and NRAS that led to a diagnosis of MDS/MN-DS. Four of the patients had aberrant myeloid populations and dysplasia fitting diagnostic criteria for MDS. Establishing the clonal nature of the disease either by karyotype/FISH or NGS may help with the identification, treatment and prognostication of this unique patient population, and may aid in the diagnosis of MN-DS, which may be challenging in patients with DS once they have recovered from TAM. Disclosures No relevant conflicts of interest to declare.


Blood ◽  
2020 ◽  
Author(s):  
Brunangelo Falini ◽  
Lorenzo Brunetti ◽  
Maria Paola Martelli

Mutations of the nucleophosmin (NPM1) gene, encoding for a nucleolar multifunctional protein, occur in about one-third of adult acute myeloid leukemia (AML). NPM1-mutated AML exhibits unique molecular, pathological and clinical features, that led to its recognition as distinct entity in the 2017 World Health Organization (WHO) classification of myeloid neoplasms. Although WHO criteria for the diagnosis of NPM1-mutated AML are well established, its distinction from other AML entities may be sometimes difficult. Moreover, the percentage of blasts required to diagnose NPM1-mutated AML remains controversial. According to the European LeukemiaNet (ELN), determining the mutational status of NPM1 (together with FLT3) is mandatory for accurate relapse risk assessment. NPM1 mutations are ideal targets for measurable residual disease (MRD) monitoring since they are AML-specific, frequent, very stable at relapse and do not drive clonal hematopoiesis of undetermined significance. MRD monitoring by quantitative PCR of NPM1 mutant transcripts, possibly combined with the ELN genetic-based risk stratification, can guide therapeutic decisions at post-remission stage. Furthermore, immunohistochemistry can be very useful in selected situations, such as diagnosis of NPM1-mutated myeloid sarcoma. Herein, we present four illustrative cases of NPM1-mutated AML, with the aim to address important issues on the biology, diagnosis and therapy of this common form of leukemia.


2018 ◽  
Vol 143 (1) ◽  
pp. 13-22 ◽  
Author(s):  
Juehua Gao ◽  
Shunyou Gong ◽  
Yi-Hua Chen

Context.— Myeloid neoplasms with familial occurrence have been rarely reported in the past. With the advance of molecular technology and better understanding of the molecular pathogenesis of myeloid neoplasms, investigating the genetic causes of familial acute myeloid leukemia or myelodysplastic syndrome has become feasible in the clinical setting. Recent studies have identified a rapidly expanding list of germline mutations associated with increased risks of developing myeloid neoplasm in the affected families. It is important to recognize these entities, as such a diagnosis may dictate a unique approach in clinical management and surveillance for the patients and carriers. Objective.— To raise the awareness of myeloid neoplasms arising in the setting of familial inheritance among practicing pathologists. Data Sources.— Based on recent literature and the 2016 revision of the World Health Organization classification of hematopoietic neoplasms, we provide an up-to-date review of myeloid neoplasm with germline predisposition. Conclusions.— This short review focuses on the clinical, pathologic, and molecular characterization of myeloid neoplasm with germline predisposition. We emphasize the important features that will help practicing pathologists to recognize these newly described entities.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1217-1217
Author(s):  
Naveen Premnath ◽  
Stephen Chung ◽  
Suleyman Y Goksu ◽  
Prapti Patel ◽  
Ruth Ikpefan ◽  
...  

Abstract Background: Vitamin C is an essential water-soluble vitamin required for many redox reactions in our body and its deficiency causes scurvy, a well characterized disease with multiple hematological manifestations. Studies dating back to 1950's demonstrated that patients with myeloid neoplasms tend to have lower plasma levels of vitamin C than healthy controls. Recent studies have shown that as much as 80% of patients with hematological malignancies in a cohort from Denmark had low vitamin C levels. Myeloid neoplasms tend to harbor mutations in epigenetic regulators which play a role in DNA methylation. One such mutation commonly seen in myeloid neoplasms and clonal hematopoiesis of indeterminate potential (CHIP) is TET2 for which vitamin C serves as a cofactor. There is a scarcity of clinical data on patients with low vitamin C level in myeloid neoplasms. Our study investigated the rates of vitamin C deficiency and the disease clinical and genomic characteristics associated with it at our center. Methods: We retrospectively collected data from a prospectively maintained list of patients treated for myeloid neoplasms at a large tertiary cancer center on whom vitamin C levels where serially collected during the study period. We obtained multiple baseline characteristics at the time of diagnosis including cytogenetic and molecular mutational data. Baseline characteristics were defined using descriptive statistics. Categorical variables were compared using a Fisher's exact test and continuous variables were analyzed using Mann Whitney U test for statistical significance. Institutional review board approval was obtained for the study. Statistical analysis was done using R Studio version 1.4.1717. Results: A total of 50 patients with myeloid neoplasms were identified with vitamin C levels available at least once during the study period. Nine (18%) patients had a low vitamin C level (LOW) defined as less than 0.4 mg/dl as per the Mayo lab testing with a reference range between 0.4 to 2.0 mg/dl. Baseline characteristics of patients with low vitamin C level and patients with normal vitamin C level (NORMAL) are shown in Table 1. The median vitamin C level in the LOW group was 0.2 mg/dl and NORMAL group was 1 mg/dl (p &lt;0.001). The median age at diagnosis for patients in the LOW cohort was 64 years compared to 72 years for patients with normal vitamin C level (p = 0.015). Twenty-two (53.6%) of patients were female in the NORMAL cohort while six patients (66.7%) were females in the LOW cohort (p=NS). In the vitamin C LOW group only 55% of the patients were white compared to 83% in the NORMAL group (p = 0.093). The majority of patients in the Vit C LOW group had acute myeloid leukemia (AML) 44.5%, compared to 9.8% in the group with normal vitamin C levels (p = 0.03). Median white blood cell count, platelet counts, peripheral blast count and bone marrow blast count were not statistically significant amongst the 2 groups. Majority of patients in both groups 56.1% (NORMAL) vs 77.8% (LOW) had normal cytogenetics at the time of diagnosis (p = 0.284). There was a higher tendency to harbor ASXL1 and IDH2 mutation in the cohort with LOW levels 44.5% (p = 0.09) and 22.2% (p value = 0.143) compared to 17% and 4.8% respectively in the NORMAL cohort. Conclusions: Our analysis of the baseline characteristics of patients with myeloid neoplasms with vitamin C levels reveals interesting findings including a lower age at diagnosis for patients with low vitamin C levels and higher proportion of patients with acute myeloid leukemia compared to the cohort with normal levels. We also noted a higher tendency for occurrence of certain molecular mutations including ASXL1 and IDH2 among the patients with low vitamin C level. With recent papers implicating the role of ASXL1 in leukaemogenesis these findings suggest the hypothesis that vitamin C deficiency could accelerate clonal evolution with a higher tendency to transform into acute leukemia at a lower age. Further multi-institutional studies are needed to understand the relevance of low vitamin C level in myeloid neoplasms and the role of therapeutic vitamin C supplementation to retard leukaemogenesis. Figure 1 Figure 1. Disclosures Patel: Celgene-BMS: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; PVI: Honoraria. Awan: Cardinal Health: Consultancy; Abbvie: Consultancy; Merck: Consultancy; Beigene: Consultancy; Johnson and Johnson: Consultancy; Astrazeneca: Consultancy; BMS: Consultancy; Janssen: Consultancy; Genentech: Consultancy; Dava Oncology: Consultancy; Verastem: Consultancy; ADCT therapeutics: Consultancy; Incyte: Consultancy; MEI Pharma: Consultancy; Karyopharm: Consultancy; Kite pharma: Consultancy; Celgene: Consultancy; Gilead sciences: Consultancy; Pharmacyclics: Consultancy. Anderson: Celgene, BMS, Janssen, GSK, Karyopharm, Oncopeptides, Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Madanat: Blue Print Pharmaceutical: Honoraria; Stem line pharmaceutical: Honoraria; Onc Live: Honoraria; Geron Pharmaceutical: Consultancy.


Blood ◽  
2009 ◽  
Vol 114 (26) ◽  
pp. 5342-5351 ◽  
Author(s):  
Karl J. Aichberger ◽  
Karoline V. Gleixner ◽  
Irina Mirkina ◽  
Sabine Cerny-Reiterer ◽  
Barbara Peter ◽  
...  

Abstract Systemic mastocytosis (SM) is a myeloid neoplasm involving mast cells (MCs) and their progenitors. In most cases, neoplastic cells display the D816V-mutated variant of KIT. KIT D816V exhibits constitutive tyrosine kinase (TK) activity and has been implicated in increased survival and growth of neoplastic MCs. Recent data suggest that the proapoptotic BH3-only death regulator Bim plays a role as a tumor suppressor in various myeloid neoplasms. We found that KIT D816V suppresses expression of Bim in Ba/F3 cells. The KIT D816–induced down-regulation of Bim was rescued by the KIT-targeting drug PKC412/midostaurin. Both PKC412 and the proteasome-inhibitor bortezomib were found to decrease growth and promote expression of Bim in MC leukemia cell lines HMC-1.1 (D816V negative) and HMC-1.2 (D816V positive). Both drugs were also found to counteract growth of primary neoplastic MCs. Furthermore, midostaurin was found to cooperate with bortezomib and with the BH3-mimetic obatoclax in producing growth inhibition in both HMC-1 subclones. Finally, a Bim-specific siRNA was found to rescue HMC-1 cells from PKC412-induced cell death. Our data show that KIT D816V suppresses expression of proapoptotic Bim in neoplastic MCs. Targeting of Bcl-2 family members by drugs promoting Bim (re)-expression, or by BH3-mimetics such as obatoclax, may be an attractive therapy concept in SM.


2007 ◽  
pp. 80-92
Author(s):  
A. Kireev

The paper studies the problem of raiders activity on the market for corporate control. This activity is considered as a product of coercive entrepreneurship evolution. Their similarities and sharp distinctions are shown. The article presents the classification of raiders activity, discribes its basic characteristics and tendencies, defines the role of government in the process of its transformation.


2015 ◽  
Vol 24 (2) ◽  
pp. 203-213 ◽  
Author(s):  
Federica Furfaro ◽  
Cristina Bezzio ◽  
Sandro Ardizzone ◽  
Alessandro Massari ◽  
Roberto De Franchis ◽  
...  

The treatment of ulcerative colitis (UC) has changed over the last decade. It is extremely important to optimize the therapies which are available nowadays and commonly used in daily clinical practice, as well as to stimulate the search for more powerful drugs for the induction and maintenance of sustained and durable remission, thus preventing further complications. Therefore, it is mandatory to identify the patients' prognostic variables associated with an aggressive clinical course and to test the most potent therapies accordingly.To date, the conventional therapeutic approach based on corticosteroids, salicylates (sulfasalazine, 5-aminosalicylic acid) or immunosuppressive agents is commonly used as a first step to induce and to maintain remission. However, in recent years, knowledge of new pathogenetic mechanisms of ulcerative colitis have allowed us to find new therapeutic targets leading to the development of new treatments that directly target proinflammatory mediators, such as TNF-alpha, cytokines, membrane migration agents, cellular therapies.The aim of this review is to provide the most significant data regarding the therapeutic role of drugs in UC and to give an overview of biological and experimental drugs that will become available in the near future. In particular, we will analyse the role of these drugs in the treatment of acute flare and maintenance of UC, as well as its importance in mucosal healing and in treating patients at a high risk of relapse.


Author(s):  
Petar Halachev ◽  
Victoria Radeva ◽  
Albena Nikiforova ◽  
Miglena Veneva

This report is dedicated to the role of the web site as an important tool for presenting business on the Internet. Classification of site types has been made in terms of their application in the business and the types of structures in their construction. The Models of the Life Cycle for designing business websites are analyzed and are outlined their strengths and weaknesses. The stages in the design, construction, commissioning, and maintenance of a business website are distinguished and the activities and requirements of each stage are specified.


2020 ◽  
Vol 21 (9) ◽  
pp. 892-901 ◽  
Author(s):  
Ana Luiza Ataide Carneiro de Paula Gonzaga ◽  
Vitória Andrade Palmeira ◽  
Thomas Felipe Silva Ribeiro ◽  
Larissa Braga Costa ◽  
Karla Emília de Sá Rodrigues ◽  
...  

Background: Pediatric tumors remain the highest cause of death in developed countries. Research on novel therapeutic strategies with lesser side effects is of utmost importance. In this scenario, the role of Renin-Angiotensin System (RAS) axes, the classical one formed by angiotensinconverting enzyme (ACE), Angiotensin II and AT1 receptor and the alternative axis composed by ACE2, Angiotensin-(1-7) and Mas receptor, have been investigated in cancer. Objective: This review aimed to summarize the pathophysiological role of RAS in cancer, evidence for anti-tumor effects of ACE2/Angiotensin-(1-7)/Mas receptor axis and future therapeutic perspectives for pediatric cancer. Methods: Pubmed, Scopus and Scielo were searched in regard to RAS molecules in human cancer and pediatric patients. The search terms were “RAS”, “ACE”, “Angiotensin-(1-7)”, “ACE2”, “Angiotensin II”, “AT1 receptor”, “Mas receptor”, “Pediatric”, “Cancer”. Results: Experimental studies have shown that Angiotensin-(1-7) inhibits the growth of tumor cells and reduces local inflammation and angiogenesis in several types of cancer. Clinical trials with Angiotensin-( 1-7) or TXA127, a pharmaceutical grade formulation of the naturally occurring peptide, have reported promising findings, but not enough to recommend medical use in human cancer. In regard to pediatric cancer, only three articles that marginally investigated RAS components were found and none of them evaluated molecules of the alternative RAS axis. Conclusion: Despite the potential applicability of Angiotensin-(1-7) in pediatric tumors, the role of this molecule was never tested. Further clinical trials are necessary, also including pediatric patients, to confirm safety and efficiency and to define therapeutic targets.


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