Aggressive natural killer leukemia (ANKL)

2017-01-01   Anwar N Mohamed 

1.Cytogenetics laboratory, Pathology Department, Detroit Medical Center, Wayne State University School of Medicine, Detroit, MI USA; amohamed@dmc.org

Abstract

Review of the cytogenetics abnormalities and genes involved in aggressive natural killer leukemia (ANKL) which is a rare form of leukemia mostly reported in East Asia.

Clinics and Pathology

Note

Aggressive natural killer leukemia (ANKL), previously known as "large granular lymphocyte (LGL) leukemia", is a rare neoplastic proliferation of mature natural killer (NK) cells described in the WHO classification of 2008 as a distinct entity separated it from T-cell LGL leukemia . The NK leukemic infiltration is predominantly systemic, involving the blood, bone marrow, liver, spleen, and less frequently, lymph nodes. ANKL has a rapidly fatal clinical course with a median survival of around 2 months (Suzuki et al, 2004).

Phenotype stem cell origin

Morphologically, the leukemic NK cells are slightly larger than normal LGLs. There is an ample amount of pale or slightly basophilic cytoplasm containing fine or coarse azurophilic granules. Bone marrow shows massive or focal infiltration by NK leukemic cells that can be intermingled reactive histiocytes with hemophagocytosis. In tissue sections, NK cells show diffuse or patchy destructive infiltrate. Necrosis, apoptosis, angioinvasion, and angiodestruction are common findings.
It is believed that ANKL originates from mature NK cells. The neoplastic NK cells are typically CD2+, surface CD3-, cytoplasmic CD3ε +, CD56+, and EBV+ with germline configuration of T-cell receptor (TCR) and immunoglobulin (Ig) genes. The exclusive expression of CD2 and CD56 and the absence of CD3 and TCRs in ANKL reflect its NK-cell origin. A high expression rate of CD16 (75%) is also characteristic of ANKL (Li C et al 2014). CD16 is usually not expressed in other NK neoplasms, suggesting that CD16 is a specific marker for ANKL. Cases of ANKL are also positive for cytotoxic molecules and found to have high serum levels of CXCR1, CCR5 and soluble Fas ligand, suggesting that the chemokine system plays an important role in the systemic infiltration of NK leukemic cells and liver dysfunction (Makishima H et al, 2007).

Etiology

ANKL is almost always associated with Epstein-Barr virus (EBV) infection. EBV plays a role in the pathobiology of ANKL and is considered responsible for its aggressive clinical features.

Epidemiology

This rare leukemia has a distinct geographic distribution with the most prevalence among East Asian populations. A fewer than 200 cases have been described in the literature, as a small series or single case report. The disease most commonly affects young to middle aged adults with a median age of 40 years. Both sexes are affected with a slight male predominance (Lima, M 2013; Zhang et al 2014).

Clinics

Patients usually present extremely ill with high fever, significant weight loss, cytopenia, jaundice and abnormal liver function. Hepatosplenomegaly is often massive accompanied by lymphadenopathy but less commonly skin lesions. Involvement of the gastrointestinal tract is present in many patients, and infiltration of leukemic NK cells into the cerebrospinal and peritoneal fluids, with clinical ascites, has been reported. The hemophagocytic syndrome is frequent at diagnosis or during the disease course, resulting from uncontrolled monocyte/macrophage activation in response to cytokines produced by the neoplastic NK-cells. Despite treatment, ANKL is rapidly progressive disease and most patients die within few weeks from disseminated intravascular coagulation and multi-organ failure (Liang and Graham 2008; Lima, 2013).

Treatment

ANKL is refractory to the available chemotherapies. L-asparaginase containing chemotherapy regimen followed by allogeneic stem cell transplantation appears to slightly prolong overall survival, but relapse is almost inevitable (Ishida F, 2012).

Prognosis

ANKL is a dismal disease with an almost uniform mortality. Survival is measured in days to weeks. The overall median survival is less than 2 months.

Genes Involved and Proteins

Note
Karube at al found that the 6q21 region encompassing POPDC3, PREP, PRDM1, ATG5, AIM1, LACE1, and FOXO3 was the most frequently deleted region of the whole genome. Both FOXO3 and PRDM1expression were down-regulated in most NK-cell neoplasms compared with normal NK normal cells. The seven candidate genes were transduced into NK cell lines and forced re-expression was induced. Re-expression of FOXO3 and PRDM1 in NK cell lines suppressed cellular proliferation, but this was not the case after re-expression of the other genes. Therefore, PRDM1 and FOXO3 are considered to be tumor suppressor genes play an important role in the pathogenesis of NK-cell neoplasms (Karube K et al 2011).
Yamanaka, et al study showed that dysregulation of microRNAs (miRNAs) has a significant role in the pathogenesis of NK-cell neoplasms. They demonstrated overexpression of two miRNA " MIR21and MIR155" in NK-cell lymphoma/leukemia primary specimens and cell lines. These two miRNAs act through PTEN and INPP5D (SHIP1), respectively, to regulate AKT1, a serine-threonine kinase involved in cell survival and proliferation. No translocations or genomic amplifications of the miR-2/17q23 or miR-155/12q21 locus have been identified in NK neoplasms. Recent reports suggest that EBV infection can lead directly to up-regulation of miR-21 and miR-155 which might be the first-hit genetic alterations in NK-cell pathogenesis. Finally, they proposed targeting miR-21 and/or miR-155 may represent a useful approach to treating NK-cell lymphoma/ leukemia (Yamanaka, et al, 2009).

Highly cited references

Pubmed IDYearTitleCitations
357378602022Economic burden of interstitial lung disease in a commercially insured population with Sjögren syndrome in the United States.0
357287972022Safety and efficacy of early vitamin D supplementation in critically ill extremely preterm infants: an ancillary study of a randomized trial.0
357264272022Prevalence and death rate of COVID-19 in systemic autoimmune diseases in the first three pandemic waves. Relationship to disease subgroups and ongoing therapies.0
357108502022Building reliable radiomic models using image perturbation.0
357099662022Generation of antagonistic monoclonal antibodies against the neoepitope of active mouse interleukin (IL)-18 cleaved by inflammatory caspases.0
356984272022The pattern of primary headache in the North India population: a hospital-based study.0
356953342022Janus kinase inhibitors for the treatment of COVID-19.0
356899602022Assessment of rabies immune globulin dose rounding at a university health system.0
356880502022Association between lung cancer screening and smoking cessation.0
356794872022Triple-Wavelength Lasing with a Stabilized β-LaBSiO5:Nd3+ Crystal.0
356777322022Baricitinib in hospitalised patients with COVID-19: A meta-analysis of randomised controlled trials.0
356431562022Polylactic acid nanocomposites containing functionalized multiwalled carbon nanotubes as antimicrobial packaging materials.0
355510182022Reference values for the tri-ponderal mass index and its association with cardiovascular risk factors in Brazilian adolescents aged 12 to 17 years.0
355255232022Multi-parametric MRI-based radiomics for the diagnosis of malignant soft-tissue tumor.0
355026872022Proprotein convertase subtilisin/kexin type 9 is associated with atherosclerosis in patients with Behcet's disease.0
355022962022Probable cross-corridor transmission of SARS-CoV-2 due to cross airflows and its control.0
354621842022Gastroesophageal reflux disease and dental erosion: The role of bile acids.0
354528692022Major gastrointestinal bleeding in patients receiving anticoagulant therapy for venous thromboembolism.0
354134642022Characteristics of human leptospirosis in three different geographical and climatic zones of Vietnam: a hospital-based study.0
353859752022Clinical use of low-dose parenteral anticoagulation, incidence of major bleeding and mortality: a multi-centre cohort study using the French national health data system.0
353030552022CALL-K score: predicting the need for renal replacement therapy in cardiogenic shock.0
352762022022Access to Urological Care for Medicaid-Insured Patients at Urology Practices Acquired by Private Equity Firms.0
352610692022Endoscopic re-intervention after stent-in-stent versus side-by-side bilateral self-expandable metallic stent deployment.0
351822052022Clinical and therapeutic variables may influence the association between infarct core predicted by CT perfusion and clinical outcome in acute stroke.0
350411152022Serum NfL associated with anti-NMDA receptor encephalitis.0
349494572022Early prediction of clinical deterioration using data-driven machine-learning modeling of electronic health records.0
347893912022Blowing time ratio and high-resolution manometry to evaluate swallowing function of patients with oral and oropharyngeal cancer.0
347674692022Multi-Institutional Validation of a Mammography-Based Breast Cancer Risk Model.1
347117632022Prevalence and treatment of neuropathic pain diagnoses among U.S. nursing home residents.0
342190442022Pancreatic ductal adenocarcinoma and invasive intraductal papillary mucinous tumor: Different prognostic factors for different overall survival.1
335177102022Emergency Medical Service Transport Time and Trauma Outcomes at an Urban Level 1 Trauma Center: Evaluation of Prehospital Emergency Medical Service Response.1
335146792022Surgical curriculum concordance: requiem for the educational dream.1
331677332022Sustainable, affordable and functional: reimagining prosthetic liners in resource limited environments.2
301683082022Drug-eluting stents for the treatment of complex femoro-popliteal disease: a systematic review and meta-analysis.0
357359682022Mobile-PolypNet: Lightweight Colon Polyp Segmentation Network for Low-Resource Settings.0
357305162022Letter to the Editor: Rethinking The Cost Of Antipsychotic Treatment: The Average Cost Of The Drugs Used In Turkey In 2020.0
357272772022Effect of MRI-Guided Fibrosis Ablation vs Conventional Catheter Ablation on Atrial Arrhythmia Recurrence in Patients With Persistent Atrial Fibrillation: The DECAAF II Randomized Clinical Trial.0
357182562022Safety and Short-Term Outcomes of Anatomic versus Reverse Total Shoulder Arthroplasty in an Ambulatory Surgery Center.0
357098272022Clinical Outcomes of Repeated Radioactive Iodine Therapy for Graves' Disease.0
357086862022Development and Validation of a Deep Learning Model to Predict the Occurrence and Severity of Retinopathy of Prematurity.0
357034122022Comparison of Outcomes for One-View Asymmetries Recalled From Digital Breast Tomosynthesis Versus Full-Field Digital Mammography Screening Examinations.0
356678892022Accuracy of 2 direct digital scanning techniques-intraoral scanning and stereophotogrammetry-for complete arch implant-supported fixed prostheses: A prospective study.0
356666072022A proposal of drain removal criteria in hepatobiliary resection.0
356596292022Metastasis-free survival and patterns of distant metastatic disease after PSMA-PET-guided salvage radiotherapy in recurrent or persistent prostate cancer after prostatectomy.0
356360852022Safety and long-term efficacy of tonsillectomy versus subtotal tonsillectomy in children with sleep disordered breathing.0
356110932022Metagenomic mining of Indian river confluence reveal functional microbial community with lignocelluloytic potential.0
355804402022A precise efficacy determination strategy of traditional Chinese herbs based on Q-markers: Anticancer efficacy of Astragali radix as a case.0
355504532022Is the Centers for Medicare and Medicaid Services Hierarchical Condition Category Risk Adjustment Model Satisfactory for Quantifying Risk After Spine Surgery?0
355461262022In vivo localized gastrocnemius subtendon representation within the healthy and ruptured human Achilles tendon.0
355126252022A time-incorporated SOFA score-based machine learning model for predicting mortality in critically ill patients: A multicenter, real-world study.0
354215462022Association of three single nucleotide polymorphisms in interleukin 6 gene with risk of chronic obstructive pulmonary disease.0
353973892022Blood transthyretin for predicting immunoglobulin A vasculitis nephritis outcome in children.0
353587632022Factors influencing the successful connection of deliberate self-injury patients to community-based mental health centers.0
352122622022Accuracy of sleep bruxism scoring based on electromyography traces of different jaw muscles in individuals with obstructive sleep apnea.0
351688812022Long term cost comparisons of radical cystectomy versus trimodal therapy for muscle-invasive bladder cancer.1
351223342022Postoperative surgical site infection rate in patients with diabetes following Mohs micrographic surgery: a retrospective analysis.0
351017072022Gel properties transition from mono-succinylation to cross-linking of agar by attemperation with succinic anhydride.0
350798872022Intratumoral and peritumoral radiomics based on dynamic contrast-enhanced MRI for preoperative prediction of intraductal component in invasive breast cancer.0
350314872022Effect of antiseptic bathing with chlorhexidine or octenidine on central line-associated bloodstream infections in intensive care patients: a cluster-randomized controlled trial.0
349097042022Hesitancy towards Covid-19 vaccination among the healthcare workers in Iraqi Kurdistan.1
348889902022Application of Simultaneous 18 F-FDG PET With Monoexponential, Biexponential, and Stretched Exponential Model-Based Diffusion-Weighted MR Imaging in Assessing the Proliferation Status of Lung Adenocarcinoma.0
348777952022Complete blood count and cell population data parameters from the Abbott Alinity hq analyzer are useful in differentiating myelodysplastic syndromes from other forms of cytopenia.0
346939252022Mental Health and Developmental Disorder Diagnoses of Foster and Nonfoster Children Enrolled in Medicaid.0
346078112022Prediction of incident atrial fibrillation in community-based electronic health records: a systematic review with meta-analysis.1
345344112022Vasa nervorum of epicardial nerves and valves of small veins investigated in porcine heart by two types of vascular injections.0
341254502022Clapping for carers in the Covid-19 crisis: Carers' reflections in a UK survey.2
341145092022Prodromal Dementia With Lewy Bodies: Evolution of Symptoms and Predictors of Dementia Onset.0
339391382022High Neutrophil-Lymphocyte Ratio and Delta Neutrophil-Lymphocyte Ratio Are Associated with Increased Mortality in Patients with Hepatocellular Cancer.0
357223752022Development and validation of a machine-learning model for prediction of hypoxemia after extubation in intensive care units.0
357122842022Research Priorities on One Health: A Bibliometric Analysis.0
356935992022A novel seven-gene risk profile in BALF to identify high-risk patients with idiopathic pulmonary fibrosis.0
356934872022Textual Features and Risk Preference Effects on Mental Health Education Among Teenager Students in Chongqing, China.0
356924042022Non-Alcoholic Fatty Liver Disease (NAFLD) Is an Independent Risk Factor for Developing New-Onset Diabetes After Acute Pancreatitis: A Multicenter Retrospective Cohort Study in Chinese Population.0
356699322022Changes in the prevalence of polycystic ovary syndrome in China over the past decade.0
356649942022Whole Genome DNA and RNA Sequencing of Whole Blood Elucidates the Genetic Architecture of Gene Expression Underlying a Wide Range of Diseases.0
356461132022Combined Efficacy of CXCL5, STC2, and CHI3L1 in the Diagnosis of Colorectal Cancer.0
356456152022An Independent Prognostic Model Based on Ten Autophagy-Related Long Noncoding RNAs in Pancreatic Cancer Patients.0
356357602022Incidence and outcomes of thromboembolic and bleeding events in patients with liver cirrhosis in the USA.0
356254912022Obesity Does Not Influence Delayed Gastric Emptying Following Pancreatoduodenectomy.0
356172982022One in five South Africans are multimorbid: An analysis of the 2016 demographic and health survey.0
356016222022Association Between Specific Type 2 Diabetes Therapies and Risk of Alzheimer's Disease and Related Dementias in Propensity-Score Matched Type 2 Diabetic Patients.0
356001692022Effects of Otago Exercise Program on serum Interleukin-6 level in older women.0
355982112022A nem alkoholos zsírmájbetegség és a 2-es típusú cukorbetegség.0
355946152022Accuracy of Risk Estimation for Surgeons Versus Risk Calculators in Emergency General Surgery.0
355890622022Telemedicine Visits to Children During the Pandemic: Practice-Based Telemedicine Versus Telemedicine-Only Providers.0
355873502022Racial and Ethnic Differences in Rural-Urban Trends in 5-Year Survival of Patients With Lung, Prostate, Breast, and Colorectal Cancers: 1975-2011 Surveillance, Epidemiology, and End Results (SEER).0
355815092022Capturing acyltransferase(s) transforming final step in the biosynthesis of a major Iridoid Glycoside, (Picroside-II) in a Himalayan Medicinal Herb, Picrorhiza kurroa.0
355516162022Physiologically based pharmacokinetic modeling of intravenously administered nanoformulated substances.0
355466922022A Histogram Model to Predict the Risk of Bleeding from Oesophageal and Gastric Variceal Rupture in Cirrhosis.0
355373832022Differences in Thymus and Activation-Regulated Chemokine and Squamous Cell Carcinoma Antigen 2 Levels in Food Protein-Induced Enterocolitis Syndrome and Atopic Dermatitis.0
355241592022Multispectral pattern recognition measures change in drusen area in age-related macular degeneration with high congruency to expert graders.0
355048892022Adverse events associated with JAK inhibitors in 126,815 reports from the WHO pharmacovigilance database.0
354920142022Predictive Ability of the MEWS, REMS, and RAPS in Geriatric Patients with SARS-CoV-2 Infection in the Emergency Department.0
354887002022[Analysis of the diagnostic efficiency of combining multiple laboratory hematological indicators in alpha-fetoprotein-negative hepatocellular carcinoma].0
353676332022ADMA and homoarginine independently predict mortality in critically ill patients.0
353666152022Study of serum miR-518 and its correlation with inflammatory factors in patients with gestational diabetes mellitus complicated with hypertensive disorder complicating pregnancy.0
353536462022Interleukin 17A rs2275913 polymorphism is associated with susceptibility to systemic lupus erythematosus: A meta and trial sequential analysis.0
352765452022Implementation of a geriatric emergency medicine assessment team decreases hospital length of stay.1
352647252022Whole-genome sequencing reveals novel ethnicity-specific rare variants associated with Alzheimer's disease.0
350906382022Safety and immunogenicity of an AS03-adjuvanted SARS-CoV-2 recombinant protein vaccine (CoV2 preS dTM) in healthy adults: interim findings from a phase 2, randomised, dose-finding, multicentre study.2

Bibliography

Pubmed IDLast YearTitleAuthors
223606792012Aggressive natural killer cell leukemia: therapeutic potential of L-asparaginase and allogeneic hematopoietic stem cell transplantation.Ishida F et al
216905542011Identification of FOXO3 and PRDM1 as tumor-suppressor gene candidates in NK-cell neoplasms by genomic and functional analyses.Karube K et al
245248772014Abnormal immunophenotype provides a key diagnostic marker: a report of 29 cases of de novo aggressive natural killer cell leukemia.Li C et al
182865252008Natural killer cell neoplasms.Liang X et al
238163482013Aggressive mature natural killer cell neoplasms: from epidemiology to diagnosis.Lima M et al
171236042007Chemokine system and tissue infiltration in aggressive NK-cell leukemia.Makishima H et al
160499162005Genome-wide array-based comparative genomic hybridization of natural killer cell lymphoma/leukemia: different genomic alteration patterns of aggressive NK-cell leukemia and extranodal Nk/T-cell lymphoma, nasal type.Nakashima Y et al
119995602002Analysis of chromosome 6q deletion in EBV-associated NK cell leukaemia/lymphoma.Ohshima K et al
105502951999Comparative genomic hybridization analysis of natural killer cell lymphoma/leukemia. Recognition of consistent patterns of genetic alterations.Siu LL et al
149610412004Aggressive natural killer-cell leukemia revisited: large granular lymphocyte leukemia of cytotoxic NK cells.Suzuki R et al
104393611999Cytogenetic abnormalities in natural killer cell lymphoma/leukaemia--is there a consistent pattern?Wong KF et al
196411832009Aberrant overexpression of microRNAs activate AKT signaling via down-regulation of tumor suppressors in natural killer-cell lymphoma/leukemia.Yamanaka Y et al
250317712014Six cases of aggressive natural killer-cell leukemia in a Chinese population.Zhang Q et al

Citation

Anwar N Mohamed

Aggressive natural killer leukemia (ANKL)

Atlas Genet Cytogenet Oncol Haematol. 2017-01-01

Online version: http://atlasgeneticsoncology.org/haematological/1690/aggressive-natural-killer-leukemia-(ankl)

External Links