transforming-growth-factor-beta and Blast-Crisis

Extensive bone marrow necrosis and symptomatic hypercalcemia have been described independently as rare complications of chronic myeloid leukemia. Here we report a 66-year-old man who developed B cell blastic transformation 10 years after diagnosis of CML in the chronic phase. Extensive bone marrow necrosis and symptomatic hypercalcemia concurrently developed after transformation, with development of disseminated intravascular coagulation and multifocal osteolysis. Most necrotic cells were readily identifiable as blasts. Mediators related to hypercalcemia, including prostaglandin E2, transforming growth factor-alpha and transforming growth factor-beta, were significantly elevated in the serum. As far as we know, this is the first case report of chronic myeloid leukemia concurrently developing bone marrow necrosis and hypercalcemia; this association was not reported in other types of leukemia or bone marrow malignancies.

Topics: Blast Crisis; Bone Marrow; Dinoprostone; Disseminated Intravascular Coagulation; Fatal Outcome; Humans; Hypercalcemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Necrosis; Osteolysis; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

To investigate the expression and significance of regulatory T cells (Tregs), FoxP3 and transforming growth factor-β (TGF-β) in different phase of chronic myeloid leukemia (CML).. Peripheral blood of 73 CML patients in Department of Hematology, Heze Municipal Hospital from March 2018 to March 2021 were collected. According to patient's period in CML, they were divided into ND CML group (newly diagnosed), CP CML group (chronic period), and BP CML group (blast phase). The percentage of Tregs, expression level of. The abnormal distribution of Treg subset in different phases of CML and the significant increase of the expression level of. Treg、. 分析调节性T细胞（Treg）、叉头状转录因子P3（FoxP3 ）和转化生长因子-β（TGF-β）在慢性髓系白血病（CML）不同时期中的表达及意义。.. 收集2018年3月-2021年3月在菏泽市立医院血液内科就诊的73例CML患者的外周血，根据患者所处的CML不同时期，将患者分为初诊组、慢性期组和急变期组，应用流式细胞术检测患者Treg水平，RT-qPCR检测. Treg细胞亚群在CML不同时期中的异常分布和. 去甲氧柔红霉素联合大剂量阿糖胞苷巩固治疗首次缓解的老年急性髓系白血病的疗效分析.. 评估去甲氧柔红霉素联合大剂量阿糖胞苷作为老年急性髓系白血病（AML）患者缓解后治疗方案的疗效及安全性。.. 对2017年11月至2021年6月纳入的24例年龄≥60岁的初次诱导缓解的AML患者进行去甲氧柔红霉素联合大剂量阿糖胞苷的巩固化疗（去甲氧柔红霉素10 mg/m

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Blast Crisis; Cytarabine; Female; Forkhead Transcription Factors; Humans; Idarubicin; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Male; Middle Aged; Remission Induction; Retrospective Studies; RNA, Messenger; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

The erythromegakaryocytic cell line (LAMA-84) and the erythroeosinophilic cell line (LAMA-87) were used to study receptor expression and receptor-mediated response to monocyte/macrophage colony-stimulating factor (M-CSF) and transforming growth factor beta (TGF-beta), two modulators of cell proliferation. As demonstrated by Northern blot analysis and reverse transcriptase polymerase chain reaction (RT-PCR), c-fms and M-CSF mRNA were expressed in both cell lines. M-CSF was detected in the supernatant of both cell lines and addition of a neutralizing anti-M-CSF antibody inhibited cell growth. The two LAMA cell lines were found to express TGF-beta1, -beta2, and -beta3 mRNAs and to secrete TGF-beta mostly in latent form. Addition of anti-TGF-beta antibodies to the culture medium increased their proliferation, whereas TGF-beta1 inhibited cell proliferation by downregulating the c-myc mRNA. These results show that the proliferation of both LAMA cell lines is positively and negatively regulated by autocrine mechanisms, implying the presence of M-CSF and TGF-beta, respectively. They suggest that similar autocrine loops could be involved in the growth regulation of leukemic cells in vivo.

Topics: Animals; Blast Crisis; Blotting, Northern; Cell Division; Culture Media, Conditioned; Eosinophils; Erythrocytes; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Macrophage Colony-Stimulating Factor; Megakaryocytes; Mice; Mice, Nude; Neoplasm Transplantation; Polymerase Chain Reaction; RNA-Directed DNA Polymerase; RNA, Messenger; Transforming Growth Factor beta; Tumor Cells, Cultured

We evaluated the effects of transforming growth factor-beta 1 (TGF-beta 1) on the growth of hematopoietic progenitors in normal donors and in patients with hematologic malignancies now designed as clonal disorders of multipotential stem cells. TGF-beta 1 at 80 pM exhibited differential effects on the normal hematopoietic progenitors when cells were stimulated with different growth factors, such as G-CSF, GM-CSF, interleukin-3 (IL-3), or stem cell factor (SCF). The suppressive effect by TGF-beta 1 was increased for growth with GM-CSF, IL-3, and SCF, and growth with G-CSF was unaffected in hematologic malignancies, TGF-beta 1 suppression for growth with G-CSF was increased for essential thrombocythemia (ET) and polycythemia vera; chronic myelogenous leukemia (CML) in chronic phase; CML in accelerated phase; CML in myeloid crisis; myelodysplastic syndrome (MDS) in refractory anemia; MDS in refractory anemia with an excess of blasts; and acute myeloblastic leukemia (AML). In CML-myeloid crisis and AML, TGF-beta 1 almost completely abolished the growth, with some patient-to-patient variation. The mean ED50s for the growth of leukemic blast progenitors were 1.6, 1.2, 0.7, and 0.2 pM in the presence of G-CSF, GM-CSF, IL-3, and SCF, respectively, c-myc and c-myb antisense oligonucleotides significantly suppressed the growth of leukemic blast progenitors, but not that of clonogenic cells from normal donors and patients with ET. We also demonstrated that TGF-beta 1 inhibits mRNA expression by AML blasts for c-myc and/or c-myb. When the data are taken together, growth suppression by TGF-beta 1 appears to increase with the progression of clonal evolution in hematologic malignancies.

Topics: Base Sequence; Blast Crisis; Bone Marrow; Cell Division; Colony-Forming Units Assay; Gene Expression; Genes, myc; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Stem Cells; Interleukin-3; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Molecular Sequence Data; Oligodeoxyribonucleotides; Oncogenes; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-myb; Proto-Oncogene Proteins c-myc; Recombinant Proteins; Reference Values; RNA, Messenger; Transforming Growth Factor beta

We studied the effect of transforming growth factor-beta 1 (TGF-beta 1) on colony formation of leukemic blast progenitors from ten acute myeloblastic leukemia (AML) patients stimulated with granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), interleukin-6 (IL-6), or interleukin-1 beta (IL-1 beta). These CSFs and interleukins by themselves stimulated the proliferation of leukemic blast progenitors without adding TGF-beta 1. G-CSF, GM-CSF, and IL-3 stimulated blast colony formation in nine patients, IL-6 stimulated it in five, and IL-1 beta stimulated in four. TGF-beta 1 significantly reduced blast colony formation stimulated by G-CSF, GM-CSF, or IL-6 in all patients. In contrast, TGF-beta 1 enhanced the stimulatory effect of IL-3 on blast progenitors from three cases, while in the other seven patients TGF-beta 1 reduced blast colony formation in the presence of IL-3. To study the mechanism by which TGF-beta 1 enhanced the stimulatory effect of IL-3 on blast progenitors, we carried out the following experiments in the three patients in which it occurred. First, the media conditioned by leukemic cells in the presence of TGF-beta 1 stimulated the growth of leukemic blast progenitors, but such effect was completely abolished by anti-IL-1 beta antibody. Second, the addition of IL-1 beta in the culture significantly enhanced the growth of blast progenitors stimulated with IL-3. Third, leukemic cells of the two patients studied were revealed to secrete IL-1 beta and tumor necrosis factor-alpha (TNF-alpha) constitutively; the production by leukemic cells of IL-1 beta and TNF-alpha was significantly promoted by TGF-beta 1. Furthermore, the growth enhancing effect of TGF-beta 1 in the presence of IL-3 was fully neutralized by anti-IL-1 beta antibody. These findings suggest that TGF-beta 1 stimulated the growth of blast progenitors through the production and secretion of IL-1 beta by leukemic cells.

Topics: Aged; Aged, 80 and over; Antibodies; Antigens, CD; Blast Crisis; Cell Division; Cells, Cultured; Female; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Substances; Humans; Interleukin-1; Interleukin-3; Interleukin-6; Kinetics; Leukemia, Myeloid, Acute; Male; Middle Aged; Monocytes; Recombinant Proteins; Transforming Growth Factor beta