Analysis of CSF3R Gene Mutations and Clinical Characteristics in Patients with t(8;21) Acute Myeloid Leukemia / 中国实验血液学杂志

OBJECTIVE@#To investigate the occurrence of CSF3R mutation in patients with t(8;21) acute myeloid leukemia (AML) and its correlation with some clinical parameters.@*METHODS@#The clinical and laboratory data of 167 newly diagnosed AML patients with t(8;21) translocation were analyzed retrospectively. High-throughput DNA sequencing technology combined with Sanger sequencing method was used to detect 112 gene mutations. The occurrence of CSF3R gene mutation and its influence on the remission rate after chemotherapy were analyzed.@*RESULTS@#Among 167 patients with t(8;21) AML, 15 patients (9.0%) carried CSF3R mutations, including 6 cases of membrane proximal region mutations and 9 cases of truncation mutations in the cytoplasmic tail. The most common coexisting mutations of CSF3R were KIT (40.0%), TET2 (33.3%), DNMT3A (26.7%), FLT3 (20.0%), CBL (20.0%), IDH1 (13.3%), etc. Compared with the wild type, the CSF3R mutant group had a higher mutation rate of DNA methylation-related genes（P <0.001）. The median peripheral white blood cell (WBC) count of patients with CSF3R gene mutation was 5.80 (3.20-8.56)×109/L at initial diagnosis, which was significantly lower than 8.80 (5.26-19.92)×109/L of the CSF3R wild-type patients (P =0.017). There was no significant difference between the two groups in sex, median age, FAB classification, hemoglobin level, platelet count, etc. (P >0.05). The CR rate of the CSF3R gene mutation group (100%) was significantly higher than that of the wild-type group (86.8%), but the difference was not statistically significant (P >0.05). The CSF3R gene mutation group had a significantly higher CD19 positive rate and a higher -X rate than the wild group (86.7% vs 47.4%, P =0.004; 33.3% vs 13.2%, P =0.037).@*CONCLUSION@#There is a high incidence of CSF3R mutation in t (8;21) AML patients. The clinical characteristics and coexisting mutation genes of CSF3R mutation-positive patients are different from those of wild-type patients.

Impact of CSF3R Mutation on Treatment Response and Survival of Patients with Acute Myeloid Leukemia / 中国实验血液学杂志

OBJECTIVE@#To investigate the expression of CSF3R mutation in acute myeloid leukemia (AML) and analyze its clinical characteristics and prognosis.@*METHODS@#A retrospective study was conducted in 212 patients with AML who were newly diagnosed in the Second Hospital of Shanxi Medical University from January 1th 2018 to June 30th 2021, including 22 patients with CSF3R mutations as mutation group and 190 patients with CSF3R wild type ［66 cases of them were screened by propensity score matching (PSM), as control group］. The early efficacy and survival between the two groups were compared.@*RESULTS@#The median age of patients in the mutation group was 50(17-73) years old, and the ratio of male to female was 1.2:1 The main types were AML with maturation (11 cases) and acute myelomonocytic leukemia (9 cases). Prognostic stratification was carried out according to the risk stratification system of the European leukemia network in 2017, with 16 cases (72.73%) in the middle and high-risk group. At the initial diagnosis, the median count of white blood cell (WBC) was 44.75(1.30-368.71)×109/L, among which 15 cases (68.18%) were >10×109/L, and the median count of platelet (PLT) was 24(4-55)×109/L. CSF3R T618I (68.18%) was a common mutation site, which had concomitant gene mutations, in which CEBPA mutation was the most common (10 cases, 45.45%), but only existed in CSF3R T618I mutation. The CR/CRi rate was 68.18% and 71.21% in the mutant group and the control group (P >0.05), the median over all survival time was 15 months and 9 months (P >0.05), and the median disease-free survival time was 8 months and 4 months (P >0.05), respectively.@*CONCLUSION@#Most AML patients with CSF3R mutation are middle-aged patients, the main types are AML with maturation and acute myelomonocytic leukemia, and most of them have middle and high-risk prognosis. CSF3R mutation may not be an independent prognostic marker for newly diagnosed AML patients.

Colony Stimulating Factor 3 Mutations and Myeloid Malignancies / 中国医学科学院学报

Granulocyte colony stimulating factor (G-CSF) plays a major role in the proliferation, differentiation, and activation of neutrophil cell line hematopoietic cells. G-CSF exert the function depending on its binding to colony-stimulating factor 3 receptor (CSF3R), a homo-dimer receptor located on the surface of effector cells. Some recent studies have demonstrated that CSF3R mutations play a significant role in many diseases. Some of the hematopoietic diseases, especially myeloid malignancies (e.g. chronic neutrophilic leukemia) are related to the presence of various CSF3R mutations, which leads to abnormal G-CSF signal pathways. Also, the downstream kinases can be the treatment targets for these diseases. This review summarizes CSF3R mutations, mechanisms of mutations, and their contributions to the myeloid malignancies, with an attempt to further reveal the pathogenesis of myeloid malignancies, inform the diagnosis and clinical treatment of the myeloid malignancies, and provide clues for the research and development of new molecular target drugs.

T618I-Mutated Colony Stimulating Factor 3 Receptor in Chronic Neutrophilic Leukemia and Chronic Myelomonocytic Leukemia Patients who Underwent Allogeneic Stem Cell Transplantation

No abstract available.

CSF3R, ASXL1,SETBP1, JAK2 V617F and CALR mutations in chronic neutrophilic leukemia / 中华血液学杂志

<p><b>OBJECTIVE</b>To observe the CSF3R, ASXL1, SETBP1, JAK2 V617F and CALR mutations in patients with chronic neutrophilic leukemia (CNL).</p><p><b>METHODS</b>Twelve suspected "CNL" patients were retrospectively reviewed according the WHO criteria (2008). CSF3R,ASXL1,SETBP1 and CALR mutations were sequenced, and JAK2 V617F was tested by allele specific (AS)-PCR.</p><p><b>RESULTS</b>6 of 12 cases were diagnosed as CML, and all of the 6 carried. 4 of 6 patients also had ASXL1 and SETBP1 mutations and one had a CALR mutation (c.1154-1155insTTGTC). Two patients with monoclonal gammopathy with uncertain significance (MGUS) combined with CNL-like symptoms had no CSF3R, ASXL1, SETBP1, JAK2 V617F or CALR mutation. The same results were also seen in other 4 cases with secondary neutrophilic leukocytosis.</p><p><b>CONCLUSION</b>CSF3R, ASXL1 and SETBP1 mutations differential diagnosis of CNL, and should be included in the diagnostic protocol so as to improve diagnostic accuracy for CNL.</p>

Current strategies in the diagnosis and management of chronic neutrophilic leukemia / 中华医学杂志(英文版)

<p><b>OBJECTIVE</b>To review the implications for diagnosis, pathogenesis and potential for new therapeutic option for chronic neutrophilic leukemia (CNL).</p><p><b>DATA SOURCES</b>Data cited in this review were obtained mainly from PubMed and Medline from 1993 to 2013 and highly regarded older publications were also included. The terms "chronic neutrophilic leukemia" and "diagnosis" were used for the literature search.</p><p><b>STUDY SELECTION</b>We identified, retrieved and reviewed the information on the clinical and laboratory features, the new genetic findings, prognosis and disease evolution and management of CNL.</p><p><b>RESULTS</b>The discovery of high-frequency granulocyte-colony stimulating factor receptor (CSF3R) mutations in CNL identifies a new major diagnostic criterion, and lends more specificity to the World Health Organization (WHO) diagnostic criteria for CNL, which are variably applied in routine clinical practice.</p><p><b>CONCLUSIONS</b>In patients for whom the cause of neutrophilia is not easily discerned, the incorporation of CSF3R mutation testing can be a useful point-of-care diagnostic to evaluate the presence of a clonal myeloid disorder, as well as providing the potential for genetically informed therapy. The oncogenic CSF3R mutations are molecular markers of sensitivity to inhibitors of the SRC family-TNK2 and JAK kinases and may provide a new avenue for therapy.</p>

Artículos de revisión: cultivos de expansión ex vivo de células madre a partir de sangre de cordón umbilical / Reviews: hematopoietic stem cell, ex vivo expansion from umbilical cordon blood

El éxito en el enfrentamiento a las hemopatías malignas depende de la erradicación de los clones tumorales por medio de la quimioterapia y la radioterapia. Sin embargo, en determinados pacientes la capacidad de curación se muestra limitada, y se requiere la sustitución de la función medular dañada por una nueva hematopoyesis sana, a través del trasplante de médula ósea (TMO). Este tipo de terapia celular puede contar ahora con donantes alternativos obtenidos a partir de la sangre de cordón umbilical (SCU) almacenada en bancos creados en varios países. Se ha comprobado la necesidad de promover un implante más rápido que disminuya la morbimortalidad relacionada con el procedimiento y permita la generalización de su uso, y se han propuesto estrategias basadas en la expansión de las células progenitoras hematopoyéticos (CPH) ex vivo, en cultivos a partir de SCU, lo que permite su uso en trasplantes con bajo contenido celular, y para diferenciar células pertenecientes a diferentes linajes hematopoyéticos, e incluso tejidos, con diferentes objetivos: trasplante hematopoyético, soporte de la recuperación a corto plazo, inmunoterapia, terapia génica, y diferenciación a tejidos mesenquimales. En esta revisión se explica cómo, de un producto habitualmente desechado, la SCU se ha convertido en una fuente de gran interés científico por la facilidad de su colecta, la fuente "ilimitada" de donantes, la calidad biológica de sus células madre cercanas a la época embrionaria y fetal del desarrollo, y la posibilidad de un uso amplio en diferentes estrategias de expansión ex vivo para terapia celular.

Role of stem cell factor and its receptor in the pathogenesis of pediatric aplastic anemia / 华中科技大学学报（医学）（英德文版）

In order to investigate the levels of stem cell factor (SCF) and its receptor c-kit protein and mRNA in pediatric aplastic anemia (AA) and their relevance to the pathogenesis, immunocytochemical and in situ hybridization were utilized to detect the expression of SCF and its receptor c-kit gene protein and mRNA, respectively in 59 children with AA and 51 normal controls. The relationship between SCF and c-kit and the pathogenesis of AA was analyzed subsequently. The results showed that the positive rate of SCF protein and mRNA expression in children with AA was significantly lower than that in healthy controls (P 0.05). It was concluded that the expression of SCF is significantly decreased in children with AA, which may be closely associated with the pathogenesis of the AA. c-kit may be unrelated to the development of pediatric AA. Therefore, AA in children may have abnormalities at SCF/c-kit signal transduction levels.

Anemia aplástica: experiencia con 7 casos / Aplastic anemia: a report of 7 cases

La anemia aplástica (AA) es una falla medular caracterizada por pancitopenia en sangre periférica como resultado de una disminución de la producción de células sanguíneas en médula ósea. Tiene diversas etiologías y una incidencia de 2 a 4 casos por 1 000 000 niños menores de 15 años. El tratamiento de elección es el transplante de médula ósea alogénico o en su defecto la inmunosupresión con lingoglobulina o timoglobulina además de ciclosporina, metilprednisolona y factores de crecimiento hematopoyético. Se presenta la experiencia con 7 pacientes del Hospital Roberto del Río diagnosticados entre los años 1995 y 2000, edad 2 meses a 13 años, con biopsia de médula ósea compatible. Dos pacientes presentaban etiología congénita, 3 con antecedentes de hepatitis y 2 fueron considerados idiopáticos. Un paciente fue transplantado de un hermano compatible luego de recibir inmunosupresión, 3 recibieron inmunosupresión con linfo/timoglobulina además de ciclosporina y factor estimulante de colonias de granulocitos y 3 niños sólo recibieron tratamiento de sostén con metilprednisolona o factores de crecimiento. Dos pacientes fallecieron precozmente por cuadro infeccioso. Cinco pacientes están vivos con una mediana de seguimiento de 43 meses, los 4 que recibieron inmunosupresión incluido el paciente transplantado, y la paciente con anemia de Fanconi

Varying expression levels of colony stimulating factor receptors in disease states and different leukocytes

Administration of G-CSF may not always respond in rise of neutrophil counts in different patient population. In order to understand a possible inter-relationship between the G-CSF and GM-CSF induced leukocyte responses and expression levels of receptors for G-CSF (G-CSFr) and GM-CSF (GM-CSFr), the levels of each receptor and CSF were measured in patients with basophilia (8), eosinophilia (14) and bacterial infection showing neutrophilia (12) in comparison with normal healthy adults (12) and children (14). G-CSFr was expressed in neutrophils in the largest amount followed by monocytes, but GM-CSFr was expressed more in monocytes than neutrophils. Lymphocytes and basophils did not express G-CSFr or GM-CSFr. The amount of GM-CSFr in neutrophils was present less in patients with infection than normal control (P = 0.031). The neutrophils expressed more G-CSFr than GM-CSFr. The quantity of G-CSFr in eosinophil showed marked interval change, higher in acute stage. The plasma concentrations of G-CSF in patients with infection were much higher than normal adults or children (117.95 +/- 181.16 pg/ml, P < 0.05). Binding assay with excess amount of CSFs could discriminate the patient who did not show any response to G-CSF or GM-CSF administration. After incubation with excess CSFs, more receptors were blocked in children than in adults (G-CSF P = 0.024, GM-CSF P = 0.006). These results indicate that the amount of CSFr in leukocyte varies in different types of leukocyte, and changes according to the patients' condition even in the same type of leukocyte, and the CSFrs of children bind to CSFs more than those of adults.

Estudio de la clinica, patologia, estadios, evolucion del melenoma y marcadores pronosticos (PCNA y EGFR) / Study of the clinic, pathology, stadiamevolution from melanoma and prognosis makers

Se estudiaron 29 melanomas,en forma prospectiva en relacion a la exprecion del antigeno de proliferacion nuclear(PCNA)indicador de proliferacion celular y del receptor del factor de crecimiento epidermico(EGFR) responsable de estimular la hiperplasia.La PCNA mostro valores elevados y se correlaciono con los parametros habituales.El EGFR con bajo nivel de expresion,presento en el seguimiento un llamativo incremento en los niveles de invasion mas agresivos(nivel V)y en los casos del grupo de"fallecidos".

Regulación de la hematopoyesis / Hematopoyesis regulation

Las señales positivas y negativas juegan un papel trascendental en la regulación del sistema hematopoyético. En los últimos 30 años se purificaron más de 20 moléculas (glicoproteínas) con actividad biológica sobre las células progenitoras del sistema hematopoyético y sobre las células maduras circulantes. Los factores de crecimiento hematopoyéticos son las más conocidas de estas biomoléculas (citocinas como los factores estimulantes de colonias y las interleucinas), las cuales son capaces de estimular a las células de la médula ósea para producir descendencia madura. Hasta el presente se ha podido determianr no sólo la secuencia de la mayoría de estas glicoproteínas y los gene que las codifican, sino también caracterizar a las células blanco de cada uno de los factores y a sus receptores celulares. Los estudios de la interacción entre las células progenitoras hematopoyéticas y los factores que estimulan y/o inhiben su proliferación, han demostrado ser muy útiles en el desarrollo de terapias clínicas y podrían ser herramientas importantes en el análisis de la patogenia de muchas enfermedades hematológicas. Sin embargo, los mecanismos subyacentes en la producción de factores estimulantes o inhibidores y la proliferación de las células progenitoras hematopoyéticas continúan siendo escasamente conocidos