Blood Cells, Molecules, and Diseases

EPO-R+ myelodysplastic cells with ring sideroblasts produce high erythroferrone levels to reduce hepcidin expression in hepatic cells Publication date: September 2019 Source: Blood Cells, Molecules, and Diseases, Volume 78 Author(s): Shogo Miura, Masayoshi Kobune, Hiroto Horiguchi, Shohei Kikuchi, Satoshi Iyama, Kazuyuki Murase, Akari Goto, Hiroshi Ikeda, Kohichi Takada, Koji Miyanishi, Junji Kato Abstract Recently, a new erythroid regulator, erythroferrone (ERFE), which downregulates hepatic hepcidin production, has been identified. However, the relationship between ERFE and abnormal iron metabolism in MDS is unclear. In this study, we examined the level of ERFE mRNA during ex vivo erythroid differentiation using cord blood CD34+ cells and we further analyzed whether ERFE could be produced by MDS cells using a public database (GSE58831). ERFE mRNA was increased during normal erythroid differentiation. An analysis of GSE58831 indicated that ERFE expression in bone marrow (BM) MDS cells was higher than that in healthy volunteer (HV)–derived BM cells. ERFE expression significantly and positively correlated with the expression of erythropoietin (EPO) receptors (EPO-R), ALAS2 (5'-Aminolevulinate Synthase 2), STEAP3 (STEAP family member 3) and the presence of ring sideroblasts or the SF3B1 mutation. These results suggest that EPO-R+ MDS cells with ring sideroblasts or an SF3B1 mutation produce high levels of ERFE that may be associated with a reduction in hepcidin.

Pagophagia in men with iron-deficiency anemia Publication date: July 2019 Source: Blood Cells, Molecules, and Diseases, Volume 77 Author(s): James C. Barton, J. Clayborn Barton, Luigi F. Bertoli Abstract Few case series of pagophagia and iron deficiency include men. We performed a retrospective study of non-Hispanic white men with iron-deficiency anemia whose anemia and pagophagia, thrombocytosis, and thrombocytopenia (if present) resolved after iron replacement. Iron-deficiency anemia was defined as transferrin saturation (TS) <15%, serum ferritin (SF) <30 μg/L, and hemoglobin (Hb) <13.0 g/dL. We excluded men with: anemia, thrombocytosis, or thrombocytopenia due to non-iron-deficiency causes; malignancy; chronic inflammatory conditions; hemochromatosis; or creatinine >1.1 mg/dL. We computed univariate and multivariable pagophagia associations with: age; gastrointestinal bleeding; TS; SF; Hb; red blood cell (RBC) count; mean corpuscular volume (MCV); RBC distribution width (RDW); and platelet count. Median age of 41 men was 54 y (range 18–81). Fourteen men (34.1%) had pagophagia. Thirty-six men (87.8%) had gastrointestinal bleeding. Mean Hb was 9.4 ± 2.2 g/dL. Six men (14.6%) had thrombocytosis; two (4.9%) had thrombocytopenia. Logistic regression on pagophagia revealed: age (p = 0.0158; odds ratio 0.92 [95% confidence interval: 0.85, 0.99]) and platelet count (p = 0.0187; 0.98 [0.97, 1.00]) (41.4% of pagophagia occurrence; ANOVA p = 0.0053). We conclude that pagophagia occurred in 34% of men with iron-deficiency anemia and was negatively associated with age and platelet count, after adjustment for other variables.

The Growth Differentiation Factor-15 (GDF-15) levels are increased in patients with compound heterozygous sickle cell and beta-thalassemia (HbS/βthal), correlate with markers of hemolysis, iron burden, coagulation, endothelial dysfunction and pulmonary hypertension Publication date: July 2019 Source: Blood Cells, Molecules, and Diseases, Volume 77 Author(s): Katerina Larissi, Marianna Politou, Alexandra Margeli, Christos Poziopoulos, Pagona Flevari, Evangelos Terpos, Ioannis Papassotiriou, Ersi Voskaridou Abstract The clinical manifestations of Sickle Cell Disease (SCD) include episodes of vascular occlusion, chronic hemolytic anemia and frequent infections. GDF-15, a multifactorial cytokine, is a member of the transforming growth factor- superfamily. Expression of the GDF-15 gene in cardiomyocytes, vascular smooth muscle cells, and endothelial cells is strongly upregulated in response to oxidative stress, inflammation and tissue injury, while high levels of serum GDF-15 associate with ineffective erythropoiesis and may reflect a certain type of bone marrow stress or erythroblast apoptosis. In this context we aimed to evaluate GDF-15 levels in 89 patients with HbS/βthal at steady phase and in 20 apparently healthy individuals, and correlate with clinical features of the disease and markers of hemolysis, iron burden, inflammation, coagulation and endothelial dysfunction. We found that: GDF-15 levels were elevated in patients with HbS/βthal compared to controls (1980.7 ± 159.8 vs 665.4 ± 50.9 pg/mL, p < 0.0001) and correlated significantly with LDH (p < 0.001), Hepcidin-25/Ferritin molar ratio (p = 0.002), vWF:antigen (p < 0.05), HbA% (p < 0.001) and Mean Pulmonary Artery Pressure (p < 0.001). These findings demonstrate for first time an important multifactorial role of GDF-15 in patients with HbS/βthal, however, prior to its clinical usefulness, this biomarker must undergo through rigorous validation in multiple cohorts.

Autophagy-deficient mice are more susceptible to engrafted leukemogenesis Publication date: July 2019 Source: Blood Cells, Molecules, and Diseases, Volume 77 Author(s): Chaorong Ge, Ni An, Lei Li, Wen Wei, Li Ji, Na Yuan, Yixuan Fang, Li Xu, Lin Song, Jingyi Zhang, Chenglin Song, Jianrong Wang, Suping Zhang Abstract Autophagy is primarily considered as an important survival mechanism for both normal cells and cancer cells in response to metabolic stress or chemotherapy; but the role of autophagy in leukemogenesis is not fully understood. The aim of this study is to explore the role of intrinsic autophagy in the leukemogenesis of B-cell acute lymphoblastic leukemia (B-ALL). In this study, conditional knockout mice Atg7f/f;Ubc-Cre, in which an autophagy-essential gene Atg7 is universally deleted, were used as recipients, B-ALL cell line 697 was used as donor cells to generate leukemia mouse model. Compared to wild-type mice, Atg7 knockout mice were more susceptible to engrafted leukemogenesis, shown by increase in white blood cells, lymphocytes, and platelets, decrease in HSPC number and its colony-forming unit (CFU). The liver and spleen displayed hepatosplenomegaly and inflammatory cell infiltration. Furthermore, second competitive transplantation revealed dysfunction of the HSPC in Atg7-knockout leukemia mice represented by destructive self-renew ability (CFU) and reconstitution ability including decreased B220, Ter 119 cells, and increased Gr-1 cell percentage. In summary, Mice with universal deletion of Atg7 are more inclined to the occurrence of engrafted human leukemia, which is largely attributed to the deterioration of the function of HSPC in autophagy deficient mice.

Cytogenetic evolution in myeloproliferative neoplasms with different molecular abnormalities Publication date: July 2019 Source: Blood Cells, Molecules, and Diseases, Volume 77 Author(s): Seon Young Kim, Mosae Koo, Yumi Park, Hyunjin Kim, Qute Choi, Ik-Chan Song, Deog-Yeon Jo, Jimyung Kim, Gye Cheol Kwon, Sun Hoe Koo Abstract We investigated the changes in chromosomal abnormalities in myeloproliferative neoplasm (MPN) patients during long-term follow-up. In total, 28 MPN patients (22 with primary myelofibrosis and 6 with polycythemia vera) were included. Among them, 25 patients underwent serial bone marrow (BM) biopsies during disease progression, and 3 patients had cytogenetic abnormalities at initial diagnosis but lacked follow-up BM biopsies. JAK2, CALR, and MPL mutation analyses were performed. Targeted sequencing analysis was conducted in 11 patients. Among the 28 patients, 21 (75.0%) had cytogenetic abnormalities either at diagnosis (8/26) or during follow-up. The median time from the initial analysis to the appearance of additional cytogenetic abnormalities was 8.4 years. Among the chromosomal abnormalities at initial diagnosis, trisomy 8 (3/26, 11.5%) was the most frequent, followed by gain of 1q, del(20q), and del(9q) (each in 2/26). Among all chromosomal abnormalities, including those that occurred during follow-up, the most frequent was del(20q) and +1q (8/28, 28.6%), followed by del(6p) (14.3%) and trisomy 8 (10.7%). Del(20q) was more frequent in CALR-mutated patients (4/6, 66.7%) than in JAK2-mutated patients (3/19, 15.8%, P = 0.016). The presence of cytogenetic abnormalities at initial diagnosis was associated with poor prognosis. Cytogenetic evolution may provide interesting insights into the disease course.

Identification of promising prognostic genes for relapsed acute lymphoblastic leukemia Publication date: July 2019 Source: Blood Cells, Molecules, and Diseases, Volume 77 Author(s): Chai Ji, Shengliang Lin, Dan Yao, Mingyan Li, Weijun Chen, Shuangshuang Zheng, Zhengyan Zhao Abstract Purpose The present study aimed to identify the molecular mechanism of acute lymphoblastic leukemia (ALL), and explore valuable prognostic biomarkers for relapsed ALL. Methods Gene expression dataset including 59 samples from ALL survivals without recurrence (good group) and 114 samples from dead ALL patients died of recurrence (poor group) was downloaded from TCGA database. The differentially expressed genes (DEGs) were identified between good and poor groups, followed by pathway and functional enrichment analyses. Subsequently, logistic regression model and survival analysis were performed. Results In total, 637 up- and 578 down-regulated DEGs were revealed between good and poor groups. These DEGs were mainly enriched in functions including transcription and pathways like focal adhesion. Genes including alpha-protein kinase 1 (ALPK1), zinc finger protein 695 (ZNF695), actinin alpha 4 (ACTN4), calreticulin (CALR), and F-Box and leucine rich repeat protein 5 (FBXL5) were outstanding in survival analysis. Conclusion Transcription and focal adhesion might play important roles in ALL progression. Furthermore, genes including ALPK1, ZNF695, ACTN4, CALR, and FBXL5 might be novel prognostic genes for relapsed ALL.

Reversal of acquired von Willebrand syndrome with allogeneic stem cell transplant for chronic lymphocytic leukemia Publication date: July 2019 Source: Blood Cells, Molecules, and Diseases, Volume 77 Author(s): Livia Hegerova, Fiona He, Nicole D. Zantek, Gregory M. Vercellotti, Shernan G. Holtan, Mark T. Reding Abstract Acquired von Willebrand syndrome (AVWS) is a rare, potentially fatal bleeding disorder caused by low activity of von Willebrand factor (VWF) in patients without congenital deficiency. The majority of adult cases are associated with hematological malignancy, including lymphoproliferative (48%) or myeloproliferative (15%) disorders (Federici et al., 2000). Both qualitative and quantitative defects occur, due to antibody-mediated clearance or functional interference, increased proteolysis, absorption to malignant cells or platelets, or increased shear stress due to valvular defects or mechanical vascular devices (Tiede et al., 2011). The predominant mechanism for decreased or absent VWF in malignancy is autoantibodies that are inhibitory to VWF function or shorten VWF survival (Kumar et al., 2002 [3]). Antibody-mediated clearance occurs through inactivating antibody directed towards VWF, antibody binding the non-active sites of VWF, and nonspecific antibodies that form circulating immune complexes with VWF, enhancing clearance by the reticuloendothelial system (Mannucci et al., 1984). Bleeding may be very difficult to treat due to reduced half-life of VWF-concentrates.

Monocytes-neutrophils-ratio as predictive marker for failure of first induction therapy in AML Publication date: July 2019 Source: Blood Cells, Molecules, and Diseases, Volume 77 Author(s): Thomas Mika, Swetlana Ladigan, Karin Schork, Michael Turewicz, Martin Eisenacher, Wolff Schmiegel, Roland Schroers, Alexander Baraniskin Abstract Introduction Acute myeloid leukemia (AML) is, if untreated, a fatal hematologic neoplasia. Failure of the first induction chemotherapy is a hallmark for a poor prognosis. Early recognition of therapy failure is crucial for planning further therapies. Therefore, international guidelines recommend a bone marrow biopsy around day 14 after the beginning of induction therapy. Hypocellular bone marrow on day 14 is still gold standard for therapy assessment and further therapy strategy. Despite this, non-invasive ways for the evaluation of induction therapy were looked for in the past years. Methods We collected peripheral blood cell counts and routine laboratory values of patients treated with "7 + 3" induction therapy. Ratios of absolute cell counts of monocytes and neutrophils (MNR) were calculated daily, and the values were compared in patients with failure of the first induction therapy and patients with therapy response. Results 54 patients were included, 12 of which had failure of first induction therapy. The MNR following therapy was highly correlated with the bone marrow results. With the right cut-off, the MNR provides a valid and reliable tool for identification of patients with failure of first induction therapy with a sensitivity of 83.3% and a specificity of 87.8% on day 18. Conclusions We propose a novel and non-invasive method for detection of failure of first induction therapy in patients with de novo AML and "7 + 3" induction therapy. The MNR is free of cost since the required cell counts are performed routinely for each patient undergoing intensive chemotherapy.

Addendum to Letter to the Editor: Safety, efficacy, and authorization of eliglustat as a first-line therapy in Gaucher disease type 1 Publication date: July 2019 Source: Blood Cells, Molecules, and Diseases, Volume 77 Author(s): Pramod K. Mistry, Manisha Balwani, Hagit N. Baris, Hadhami Ben Turkia, T. Andrew Burrow, Joel Charrow, Gerald F. Cox, Sumita Danda, Marta Dragosky, Guillermo Drelichman, Amal El-Beshlawy, Cristina Fraga, Selena Freisens, Sebastiaan Gaemers, Evgueniy Hadjiev, Priya S. Kishnani, Elena Lukina, Pierre Maison-Blanche, Ana Maria Martins, Gregory Pastores

Screening umbilical cord blood for congenital Iron deficiency Publication date: July 2019 Source: Blood Cells, Molecules, and Diseases, Volume 77 Author(s): Brianna C. MacQueen, Robert D. Christensen, Vickie L. Baer, Diane M. Ward, Gregory L. Snow Abstract Objectives Small for gestational age infants (SGA), infants of diabetic mothers (IDM), and very low birth weight infants (VLBW) are at risk for congenital iron deficiency. We evaluated the iron status of SGA, IDM, and VLBW neonates at birth and sought mechanistic explanations in those with iron deficiency. Methods This was a prospective study. If congenital iron deficiency was present, maternal iron studies were obtained. When neonates were two weeks old, their iron status was reevaluated. Results Sixteen of 180 neonates screened were iron deficient at birth. The Body Mass Index of the 16 mothers was high. These mothers often had mild iron deficiency and measurable hepcidin levels. Two weeks after birth, neonates had improved iron measurements. Conclusions Among SGA, IDM, and VLBW neonates, maternal obesity is a risk factor for congenital iron deficiency. We speculate that elevated hepcidin levels in obese pregnant women impede iron absorption and interfere with transplacental iron transfer.