Altered Fibrinolysis in Hematological Malignances

2021 ◽  
Author(s):  
Søren Thorgaard Bønløkke ◽  
Hans Beier Ommen ◽  
Anne-Mette Hvas
Keyword(s):  
Systematic Review ◽  
Acute Promyelocytic Leukemia ◽  
Hematological Malignancies ◽  
Myeloproliferative Neoplasms ◽  
Clinical Manifestations ◽  
Promyelocytic Leukemia ◽  
Clot Lysis ◽  
Al Amyloidosis ◽  
Acute Leukemias ◽  
Increased Risk

AbstractBleeding and thrombosis are well-known complications to hematological malignancies, and changes in fibrinolysis impact both these issues. In the present systematic review, we provide an overview and discussion of the current literature in regards to clinical manifestations, diagnosis, and treatment of altered fibrinolysis in patients suffering from hematological malignancies, beyond acute promyelocytic leukemia. We performed a systematic literature search employing the databases Pubmed, Embase, and Web of Science to identify original studies investigating fibrinolysis in hematological malignancies. Studies investigating fibrinolysis in acute promyelocytic leukemia or disseminated intravascular coagulation were excluded. We identified 32 studies fulfilling the inclusion criteria. A majority of the studies were published more than two decades ago, and none of the studies examined all available markers of fibrinolysis or used dynamic clot lysis assays. In acute leukemia L-asparaginase treatment induced a hypofibrinolytic state, and prior to chemotherapy there seemed to be little to no change in fibrinolysis. In studies examining fibrinolysis during chemotherapy results were ambiguous. Two studies examining multiple myeloma indicated hypofibrinolysis prior to chemotherapy, and in another plasma cell disease, amyloid light chain-amyloidosis, clear signs of hyperfibrinolysis were demonstrated. In myeloproliferative neoplasms, the studies reported signs of hypofibrinolysis, in line with the increased risk of thrombosis in this disease. Only one study regarding lymphoma was identified, which indicated no alterations in fibrinolysis. In conclusion, this systematic review demonstrated that only sparse, and mainly old, evidence exists on fibrinolysis in hematological malignancy. However, the published studies showed a tendency toward hypofibrinolysis in myeloproliferative disorders, an increased risk of hyperfibrinolysis, and bleeding in patients with AL-amyloidosis, whereas studies regarding acute leukemias were inconclusive except with regard to L-asparaginase treatment, which induced a hypofibrinolytic state.

Extramedullary Involvement at Relapse in Acute Promyelocytic Leukemia Patients Treated or Not With All-Trans Retinoic Acid: A Report by the Gruppo Italiano Malattie Ematologiche dell’Adulto

2001 ◽  
Vol 19 (20) ◽  
pp. 4023-4028 ◽  
Author(s):  
Giorgina Specchia ◽  
Francesco Lo Coco ◽  
Marco Vignetti ◽  
Giuseppe Avvisati ◽  
Paola Fazi ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Increased Risk ◽  
Junction Type ◽  
Wbc Count

PURPOSE: Recent reports of extramedullary disease (EMD) at recurrence in acute promyelocytic leukemia (APL) have raised increasing concern about a possible role of retinoic acid (RA) therapy. PATIENTS AND METHODS: We analyzed the risk of developing EMD localization at relapse in APL patients enrolled onto two consecutive studies of the Gruppo Italiano Malattie Ematologiche dell’Adulto. The studies investigated chemotherapy alone (LAP0389) versus RA plus chemotherapy (AIDA). RESULTS: When all relapse types were taken into account, 94 (51%) of 184 patients and 131 (18%) of 740 patients who attained hematologic remission underwent relapse in the LAP0389 and AIDA studies, respectively (P < .0001). EMD localization was documented in five (5%) of 94 and 16 (12%) of 131 patients (P = .08). Hematologic and/or molecular relapse was diagnosed concomitantly in all but two patients with EMD in the AIDA study. For patients in the LAP0389 and AIDA series, the probability of EMD localization of any type at relapse was 3% and 4.5%, respectively (P = .79), while the probability of CNS involvement was 0.6% and 2% (P = .28). No significant differences were found with regard to mean WBC count and promyelocytic leukemia/retinoic acid receptor-alpha junction type in comparisons of patients with EMD and hematologic relapse. CONCLUSION: APL patients receiving all-trans retinoic acid in addition to chemotherapy have no increased risk of developing EMD at relapse as compared with those treated with chemotherapy alone.

scholarly journals Philadelphia-Negative Chronic Myeloproliferative Neoplasms during the COVID-19 Pandemic: Challenges and Future Scenarios

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4750
Author(s):  
Francesca Palandri ◽  
Massimo Breccia ◽  
Valerio De Stefano ◽  
Francesco Passamonti
Keyword(s):  
Hematological Malignancies ◽  
Myeloproliferative Neoplasms ◽  
Published Data ◽  
Future Scenarios ◽  
Risk Of Infection ◽  
Immunosuppressive Activity ◽  
Chronic Myeloproliferative Neoplasms ◽  
Increased Risk ◽  
Abrupt Discontinuation ◽  
Case Basis

An outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) started in December 2019 in China and then become pandemic in February 2020. Several publications investigated the possible increased rate of COVID-19 infection in hematological malignancies. Based on the published data, strategies for the management of chronic Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) are provided. The risk of severe COVID-19 seems high in MPN, particularly in patients with essential thrombocythemia, but not negligible in myelofibrosis. MPN patients are at high risk of both thrombotic and hemorrhagic complications and this must be accounted in the case of COVID-19 deciding on a case-by-case basis. There are currently no data to suggest that hydroxyurea or interferon may influence the risk or severity of COVID-19 infection. Conversely, while the immunosuppressive activity of ruxolitinib might pose increased risk of infection, its abrupt discontinuation during COVID-19 syndrome is associated with worse outcome. All MPN patients should receive vaccine against COVID-19; reassuring data are available on efficacy of mRNA vaccines in MPNs.

scholarly journals Clinical Significance of Mitochondrial DNA Content in Acute Promyelocytic Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3474-3474
Author(s):  
Antonio R. Lucena-Araujo ◽  
Diego A Pereira-Martins ◽  
Juan L Coelho-Silva ◽  
Isabel Weinhäuser ◽  
Pedro Luis Franca-Neto ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Complete Remission ◽  
Treatment Outcomes ◽  
Acute Promyelocytic Leukemia ◽  
Clinical Significance ◽  
Research Funding ◽  
Mononuclear Cells ◽  
Promyelocytic Leukemia ◽  
Atra Treatment ◽  
Acute Leukemias

Abstract Used in the clinical practice for more than three decades, the all-trans retinoic acid (ATRA) rendered acute promyelocytic leukemia (APL) the most curable subtype of acute myeloid leukemia, and currently, its combination with arsenic trioxide (ATO) exceeded all expectations for a chemotherapy-free protocol. In terms of metabolic importance, ATRA can also modulate the mitochondria-mediated cellular metabolism and promote a shift from a glycolytic-driven metabolism to an oxidative phosphorylation profile, although this effect has never been demonstrated in APL. As part of the cellular metabolic machinery, mitochondrial DNA (mtDNA) content has been reported to be altered in different types of solid tumors with clinical implication on patient treatment outcomes, although its clinical significance in acute leukemias has not been investigated to the same extent. Particularly in acute promyelocytic leukemia (APL), the role of mtDNA content on prognostication is completely unknown. Considering that mostly APL samples display a glycolytic-driven metabolism, it is conceivable that APL patients harboring high mtDNA content may present a better response to ATRA-based therapies. To test this hypothesis, we determined the mtDNA content in samples from patients with APL enrolled in the International Consortium on Acute Promyelocytic Leukemia study (Rego et al. Blood. 2013 Mar 14;121(11):1935-43) and analyzed its relationship to treatment outcomes. Diagnostic bone marrow (BM) mononuclear cells from 156 consecutive patients with APL (median age: 35 years, range: 18-82 years; 45% male) were obtained at diagnosis. For comparison purposes, we also included peripheral blood (PB) from 293 age- and sex-adjusted healthy volunteers. First, we determined whether mtDNA content could be compared between PB mononuclear cells and BM. To do so, we measured the mtDNA content of 22 APL patients, for whom paired samples were available at the time of diagnosis and detected a strong correlation between PB and BM samples (Pearson correlation coefficient, r=0.78, 95% confidence interval, CI: 0.54 to 0.9). Next, we used the values of mtDNA higher than the 95 th percentile of healthy subjects (≥1.63. Note: this value represents a fold change relative to healthy control) to define APL patients with high mtDNA content. Patients that presented values within the range of normal control samples (&lt;1.63) were classified as normal mtDNA content. The median follow-up among survivals was 40 months (95%CI: 34-47 months). Of the 131/156 patients who achieved complete remission, 18 patients (14%) relapsed. mtDNA content had no impact on complete remission achievement (84% for normal mtDNA versus 83% for high mtDNA; P=0.924) or overall survival (78% for normal mtDNA versus 80% for high mtDNA; P=0.69). In contrast, patients with high mtDNA content had a significantly high 5-year disease-free survival rate (86%, 95%CI: 78-95%) than patients with normal mtDNA content (61%, 95%CI: 46-82%). Considering non-relapse death as a competing cause of failure, the 5-year cumulative incidence of relapse (CIR) for patients with high and normal mtDNA content were 35% (95%CI: 16-49%) and 10% (95%CI: 2-17%), respectively. The multivariate Cox proportional hazards model showed that mtDNA content was independently associated with CIR (hazard ratio, HR: 0.31, 95%CI: 0.12-0.8) considering PETHEMA/GIMEMA risk of relapse subgroups and age as confounders. To functionally evaluate the metabolic alterations in APL cells upon ATRA treatment, NB4 cell line was treated with ATRA (1 µM) for 48 and 72 hours. In vitro analyses demonstrated (as expected) that the treatment with resulted in increased levels of myeloid maturation markers (CD11b/CD11c/CD15), with morphological changes being only observed at 72 hours. Metabolically, we observed an increase in mitochondrial mass and potential upon ATRA-treatment after 48 hours, which was also reflected by increase in the mtDNA content (2-fold increase in comparison with the vehicle). Together, these findings demonstrate an important, but not completely understood role for mtDNA content in APL. Disclosures Silveira: BMS/Celgene: Research Funding; Servier/Agios: Research Funding; Abbvie: Speakers Bureau; Astellas: Speakers Bureau. Pagnano: EMS: Other: Lecture; Jansenn: Other: Lecture; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pintpharma: Other: Lecture.

scholarly journals Regulation of the expression of annexin VIII in acute promyelocytic leukemia

Blood ◽  
1994 ◽  
Vol 84 (1) ◽  
pp. 279-286 ◽  
Author(s):  
A Sarkar ◽  
P Yang ◽  
YH Fan ◽  
ZM Mu ◽  
R Hauptmann ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Acute Promyelocytic Leukemia ◽  
Cellular Localization ◽  
Signal Transduction Pathway ◽  
Promyelocytic Leukemia ◽  
Induced Differentiation ◽  
Acute Leukemias ◽  
Nb4 Cells

Annexin VIII is a calcium-dependent phospholipid-binding protein previously identified as a blood anticoagulant based on in vitro studies. However, the physiologic function of annexin VIII remains unknown. In acute promyelocytic leukemia (APL) the annexin VIII gene is highly expressed, but its expression is undetectable in the blasts of other acute leukemias. In the present investigation, we showed using the APL-derived NB4 cell line that expression of the annexin VIII gene is regulated at the transcription level during induced differentiation by all-trans retinoic acid (ATRA). The half-life of the annexin VIII mRNA is about 5 to 6 hours, as determined by using actinomycin D as a transcription inhibitor. Analysis of the expression of annexin VIII protein in NB4 cells and in APL samples showed a consistent expression of a predominant 36-kD protein and a weak 72-kD protein. After ATRA- induced differentiation of NB4 cells, the annexin VIII protein level reduced gradually, but a detectable level persisted even after 4 days of induction. Because annexin VIII mRNA becomes undetectable after 48 hours of ATRA induction, this result indicates that annexin VIII is a relatively stable protein. A multiple tissue Northern blot analysis was performed, and we found that annexin VIII is normally expressed in the placenta and the lung. Cellular localization of the annexin VIII protein was determined by immunofluorescence staining and subcellular fractionation. These results indicated that annexin VIII is predominantly localized to the plasma membrane. The annexin VIII is neither an extracellular protein nor associated with the cell surface suggesting that it does not play a role in blood coagulation in vivo. The plasma membrane localization and its property as a phospholipase inhibitor suggests that annexin VIII may have a role in the signal transduction pathway in the APL cells.

scholarly journals Regulation of the expression of annexin VIII in acute promyelocytic leukemia

Blood ◽  
1994 ◽  
Vol 84 (1) ◽  
pp. 279-286 ◽  
Author(s):  
A Sarkar ◽  
P Yang ◽  
YH Fan ◽  
ZM Mu ◽  
R Hauptmann ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Acute Promyelocytic Leukemia ◽  
Cellular Localization ◽  
Signal Transduction Pathway ◽  
Promyelocytic Leukemia ◽  
Induced Differentiation ◽  
Acute Leukemias ◽  
Nb4 Cells

Abstract Annexin VIII is a calcium-dependent phospholipid-binding protein previously identified as a blood anticoagulant based on in vitro studies. However, the physiologic function of annexin VIII remains unknown. In acute promyelocytic leukemia (APL) the annexin VIII gene is highly expressed, but its expression is undetectable in the blasts of other acute leukemias. In the present investigation, we showed using the APL-derived NB4 cell line that expression of the annexin VIII gene is regulated at the transcription level during induced differentiation by all-trans retinoic acid (ATRA). The half-life of the annexin VIII mRNA is about 5 to 6 hours, as determined by using actinomycin D as a transcription inhibitor. Analysis of the expression of annexin VIII protein in NB4 cells and in APL samples showed a consistent expression of a predominant 36-kD protein and a weak 72-kD protein. After ATRA- induced differentiation of NB4 cells, the annexin VIII protein level reduced gradually, but a detectable level persisted even after 4 days of induction. Because annexin VIII mRNA becomes undetectable after 48 hours of ATRA induction, this result indicates that annexin VIII is a relatively stable protein. A multiple tissue Northern blot analysis was performed, and we found that annexin VIII is normally expressed in the placenta and the lung. Cellular localization of the annexin VIII protein was determined by immunofluorescence staining and subcellular fractionation. These results indicated that annexin VIII is predominantly localized to the plasma membrane. The annexin VIII is neither an extracellular protein nor associated with the cell surface suggesting that it does not play a role in blood coagulation in vivo. The plasma membrane localization and its property as a phospholipase inhibitor suggests that annexin VIII may have a role in the signal transduction pathway in the APL cells.

Comprehensive Characterization of Cytogenetic and Mutational Analysis of Acute Promyelocytic Leukemia: Is PML-Rara Everything?

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1404-1404
Author(s):  
Hassan Awada ◽  
Jibran Durrani ◽  
Tariq Zuheir Kewan ◽  
Ashwin Kishtagari ◽  
Valeria Visconte ◽  
...  
Keyword(s):  
Acute Promyelocytic Leukemia ◽  
Cellular Differentiation ◽  
Mutational Analysis ◽  
Chromosomal Abnormalities ◽  
Conflicts Of Interest ◽  
Clinical Manifestations ◽  
Promyelocytic Leukemia ◽  
Core Network ◽  
Cytogenetic Abnormalities ◽  
Frequent Mutations

Acute promyelocytic leukemia (APL) is characterized by PML-RARA fusion caused by the t(15;17)(q24;q21) translocation. Although PML-RARA fusion explains the dedifferentiation in most of APL patients, it still does not entirely represent the unique cause of all the clinical manifestations of the disease failing to determine the full leukemic phenotype. Up to 40 % of APL patients have an additional chromosomal abnormality other than PML-RARA. Murine studies have reported that additional cytogenetic abnormalities and secondary somatic mutations (for instance FLT3-ITD) might contribute to leukemia progression. Indeed, mice expressing mutant PML-RARA develop definitive leukemia after one year, suggesting that additional hits are required for transformation. Moreover, no distinct genetic signature has been characterized by next generation sequencing (NGS). This confirms that no gene has been reproducibly identified. APL respond to all-trans retinoic acid (ATRA) in the great majority of patients. However, one quarter of APL develop ATRA resistance suggesting that additional secondary chromosomal abnormalities might be evolving resistance. Combination of low dose arsenic, modify certain epigenetics, with ATRA decreased resistance potential and improved response. In the line with other possible factors involved in ATRA resistance, is the broad nature of the targets of ATRA. A molecular core network of ATRA's targets has been clustered in differentiation, growth factors and nuclear receptors possibly cooperating with PML-RARA and additional chromosomal abnormalities. Herein, we aimed to characterize the gene mutations and chromosomal abnormalities playing key roles in cellular differentiation and epigenetic regulation and to correlate the occurrence of these alterations with treatment response and survival outcomes in APL. We took advantage of a large cohort of APL patients (n=145). Median age of the cohort was 50 yrs (19-85); equal gender distribution; median blood counts were: [WBC 6.2 x 109/L (0.4-155); 37% had leukopenia], hemoglobin [9.8 g/dL (2.7-16.2); 32% had anemia] and platelets [29 x 109/L (range of 0-228); 93% had thrombocytopenia]. In terms of karyotype, 15% of the patients carried +8, 7% had complex karyotyping (≥3 cytogenetic abnormalities), 2% had -7/del (7q) or del (12p), 1% had -17/del(17p), and 1 patient had -5. Mutational analysis of 30 genes panel, identified 141 mutations carried by 65% (94/145) of APL patients. The most frequent mutations were observed in FLT3-ITD (61/143; 43%), WT1 (26/139; 23%), and ASXL1 (7/136; 5%) genes. Less frequent mutations were found in 3.7% of CEBPA, KRAS, and NRAS genes as well as in CBL, EZH2, TET2 (3% each) genes. Additionally, we noted that all mutations were recurrent in specific functional pathways and patients carried mutations in more than 1 gene of the same pathway. Of note, cell signaling and proliferation genes (CBL, NRAS, KRAS, KIT, FLT3) were the most frequently mutated (77/141, 55%) and impacted OS (HR: 1.7, P=0.02). Moreover, transcriptional factors which are often mutated in AML (e.g. CEBPA, TP53, NPM1, RUNX1, WT1) as well as major determinants of cell's fate were markedly mutated (38/141, 27%) suggesting that genetic impairment of signaling and transcription might contribute to the lack of differentiation observed in APL phenotypes. Mutations in epigenetic genes and histone methyltransferases (ASXL1, BCORs, DNMT3A, EZH2, IDH1/2, TET2) were also found in 18/141 (13%) while genes regulating cell proliferation and RAS family (CBL, NRAS, KRAS, NPM1) were enriched in 16/132 (12%) of APL cohort. We then analyzed the genetic picture of remission (APLRm, n=131, 90%) and relapsed (APLR, 1sr relapsed to ATRA, n=14, 10%) patients. Acknowledging the low number of APLR, we observed that molecular mutations did not make a key difference in APLRvs. APLRm [except for a complete lack of mutations in epigenetic pathways (0% vs. 13%)]. Contrarily, specific cytogenetic abnormalities were more common in APLR compared to APLRm as the case of +8 (36% vs. 11%; P= .02) and -17/del(17p) (2/14 vs. 0/131; P= .008). In sum, our study demonstrates that PML-RARA might be accompanied by additional acquired chromosomal change with a variety of genetic mutations in key pathways driving cellular differentiation. These molecular/ cytogenetic associations could determine resistance to ATRA and overall APL patients' survival. Disclosures No relevant conflicts of interest to declare.

Obesity As a Risk Factor for Acute Promyelocytic Leukemia. Results from Population and Case-Control Studies Across Western Countries and Correlation with Gene Expression in the TCGA

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 448-448 ◽  
Author(s):  
Luca Mazzarella ◽  
Edoardo Botteri ◽  
Anthony Matthews ◽  
Davide Disalvatore ◽  
Vincenzo Bagnardi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Risk Factor ◽  
Acute Promyelocytic Leukemia ◽  
Population Based ◽  
Case Control ◽  
Promyelocytic Leukemia ◽  
Transcriptional Analysis ◽  
Clinical Practice Research Datalink ◽  
Case Control Studies ◽  
Increased Risk

Abstract Background. Much uncertainty remains over the aetiology of Acute Myeloid Leukemia (AML) and of its biological subtypes, of which Acute Promyelocytic Leukemia (APL) is the best defined. In recent years, an elevated Body Mass Index (BMI) has been identified as a risk factor for several diseases. Whether BMI influences risk of developing AML and APL is not well understood. Methods. We have collated information from population-based and case-control studies conducted in four different countries. In the population-based study, we obtained data from the Clinical Practice Research Datalink, that includes primary care data of 5.2 million UK citizens. We identified APL and other leukemia cases using ICD identifiers ("APL" (n=24), "non APL-AML" (n=972), lymphoid leukemias ("LL", n=2724) and "other" (n=1850). We fitted linear models to investigate the association between BMI and any of the above leukemic classes. In the case-control studies, we analysed data from patients included in the PETHEMA (Spain, n=414) and GIMEMA (Italy, n=134) databases and patients from the USA-based AML genome sequencing study (the AML TCGA cohort with 22 additional cases characterized at Washington University-St Louis, n=42) ("case" cohorts). We then created age-, gender, ethnicity- and year of diagnosis-matched control cohorts from national BMI surveys and tested deviation of observed cases from expected controls. Lastly, we applied Quantitative Set Analysis for Gene Expression (quSAGE) analysis to investigate APL- or BMI-specific gene expression signatures from TCGA data Findings. In the UK population study, the Hazard Ratio per each 5 kg/m2 increase was 1.44 for APL (95% CI 1.0-2.08), 1.17 for non APL-AML (95% CI 1.10-1.26), 1.04 for LL (95% CI 1.0-1.09) and 1.10 for other leukemias (95% CI 1.04-1.15). In the case-control studies, BMI distribution in cases was significantly higher than expected from controls for all three cohorts: (Italy p<0.001, Spain p=0.011, USA p<0.001). quSAGE transcriptional analysis revealed significant enrichment of several pathways in APL vs other AMLs, in particular arachidonic and linoleic acid metabolism and upregulation of Insulin and IGF1 receptors. Interpretation. A higher BMI was associated with increased risk of leukemia, particularly APL; increased risk of APL was confirmed in all populations examined, irrespective of gender or ethnicity. Elevated BMI should be considered a risk factor for APL development. APL is associated with a characteristic metabolic transcriptional signature that might be responsible for some of its clinical features Disclosures Breccia: Novartis: Consultancy, Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Ariad: Honoraria; Bristol Myers Squibb: Honoraria. Lo Coco:Lundbeck: Honoraria, Speakers Bureau; Novartis: Consultancy; Baxalta: Consultancy; Pfizer: Consultancy; Teva: Consultancy, Honoraria, Speakers Bureau.

scholarly journals An Allelic Association Implicates Myeloperoxidase in the Etiology of Acute Promyelocytic Leukemia

Blood ◽  
1997 ◽  
Vol 90 (7) ◽  
pp. 2730-2737 ◽  
Author(s):  
Wanda F. Reynolds ◽  
Eric Chang ◽  
Dan Douer ◽  
Edward D. Ball ◽  
Vikas Kanda
Keyword(s):  
Acute Promyelocytic Leukemia ◽  
Myeloid Leukemia ◽  
Hypochlorous Acid ◽  
Promyelocytic Leukemia ◽  
Allelic Association ◽  
Mrna Levels ◽  
Increased Risk ◽  
Myeloid Leukemias ◽  
Alu Element ◽  
Derivatives Of

Abstract Myeloperoxidase (MPO) catalyzes a reaction between chloride and hydrogen peroxide to generate hypochlorous acid and other reactive compounds that have been linked to DNA damage. The MPO gene is expressed at high levels in normal myeloid precursors and in acute myeloid leukemias (AMLs) which are clonal derivatives of myeloid precursors that have lost the ability to differentiate into mature blood cells. Two MPO alleles differ at -463 G/A within a cluster of nuclear receptor binding sites in an Alu element. The -463 G creates a stronger SP1 binding site and retinoic acid (RA) response element (RARE) in the allele termed Sp. In this study, we investigate potential links between MPO genotype, MPO expression level, and myeloid leukemia. The SpSp MPO genotype is shown to correlate with increased MPO mRNA levels in primary myeloid leukemia cells. This higher-expressing SpSp genotype is further shown to be overrepresented in acute promyelocytic leukemia-M3 (APL-M3) and AML-M4, suggesting that higher levels of MPO are associated with an increased risk for this subset of leukemias.

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