scholarly journals An acute myeloid leukemia gene, AML1, regulates hemopoietic myeloid cell differentiation and transcriptional activation antagonistically by two alternative spliced forms.

1995 ◽  
Vol 14 (2) ◽  
pp. 341-350 ◽  
Author(s):  
T. Tanaka ◽  
K. Tanaka ◽  
S. Ogawa ◽  
M. Kurokawa ◽  
K. Mitani ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Differentiation ◽  
Transcriptional Activation ◽  
Myeloid Leukemia ◽  
Myeloid Cell ◽  
Acute Myeloid

scholarly journals Myeloid cell differentiation arrest by miR-125b-1 in myelodysplasic syndrome and acute myeloid leukemia with the t(2;11)(p21;q23) translocation

2008 ◽  
Vol 205 (11) ◽  
pp. 2499-2506 ◽  
Author(s):  
Marina Bousquet ◽  
Cathy Quelen ◽  
Roberto Rosati ◽  
Véronique Mansat-De Mas ◽  
Roberta La Starza ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Differentiation ◽  
Myeloid Leukemia ◽  
Cell Transformation ◽  
Myeloid Cell ◽  
Leukemic Cell ◽  
Granulocytic Differentiation ◽  
Leukemic Cell Lines ◽  
Acute Myeloid

Most chromosomal translocations in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) involve oncogenes that are either up-regulated or form part of new chimeric genes. The t(2;11)(p21;q23) translocation has been cloned in 19 cases of MDS and AML. In addition to this, we have shown that this translocation is associated with a strong up-regulation of miR-125b (from 6- to 90-fold). In vitro experiments revealed that miR-125b was able to interfere with primary human CD34+ cell differentiation, and also inhibited terminal (monocytic and granulocytic) differentiation in HL60 and NB4 leukemic cell lines. Therefore, miR-125b up-regulation may represent a new mechanism of myeloid cell transformation, and myeloid neoplasms carrying the t(2;11) translocation define a new clinicopathological entity.

scholarly journals WTIP upregulates FOXO3a and induces apoptosis through PUMA in acute myeloid leukemia

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Yunqi Zhu ◽  
Xiangmin Tong ◽  
Ying Wang ◽  
Xiaoya Lu
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tumor Suppressor ◽  
Transcriptional Activation ◽  
Myeloid Leukemia ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Hematologic Malignancy ◽  
Apoptotic Pathway ◽  
Acute Myeloid

AbstractAcute myeloid leukemia (AML) is an aggressive and heterogeneous clonal hematologic malignancy for which novel therapeutic targets and strategies are required. Emerging evidence suggests that WTIP is a candidate tumor suppressor. However, the molecular mechanisms of WTIP in leukemogenesis have not been explored. Here, we report that WTIP expression is significantly reduced both in AML cell lines and clinical specimens compared with normal controls, and low levels of WTIP correlate with decreased overall survival in AML patients. Overexpression of WTIP inhibits cell proliferation and induces apoptosis both in vitro and in vivo. Mechanistic studies reveal that the apoptotic function of WTIP is mediated by upregulation and nuclear translocation of FOXO3a, a member of Forkhead box O (FOXO) transcription factors involved in tumor suppression. We further demonstrate that WTIP interacts with FOXO3a and transcriptionally activates FOXO3a. Upon transcriptional activation of FOXO3a, its downstream target PUMA is increased, leading to activation of the intrinsic apoptotic pathway. Collectively, our results suggest that WTIP is a tumor suppressor and a potential target for therapeutic intervention in AML.

Targeted Alpha-Particle Immunotherapy for Acute Myeloid Leukemia

2014 ◽  
pp. e126-e131 ◽  
Author(s):  
Joseph G. Jurcic ◽  
Todd L. Rosenblat
Keyword(s):  
Acute Myeloid Leukemia ◽  
Phase I ◽  
Alpha Particle ◽  
Myeloid Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Myeloid Cell ◽  
Multicenter Trial ◽  
Alpha Particles ◽  
Particle Therapy ◽  
Acute Myeloid

Because alpha-particles have a shorter range and a higher linear energy transfer (LET) compared with beta-particles, targeted alpha-particle immunotherapy offers the potential for more efficient tumor cell killing while sparing surrounding normal cells. To date, clinical studies of alpha-particle immunotherapy for acute myeloid leukemia (AML) have focused on the myeloid cell surface antigen CD33 as a target using the humanized monoclonal antibody lintuzumab. An initial phase I study demonstrated the safety, feasibility, and antileukemic effects of bismuth-213 (213Bi)-labeled lintuzumab. In a subsequent study, 213Bi-lintuzumab produced remissions in some patients with AML after partial cytoreduction with cytarabine, suggesting the utility of targeted alpha-particle therapy for small-volume disease. The widespread use of 213Bi, however, is limited by its short half-life. Therefore, a second-generation construct containing actinium-225 (225Ac), a radiometal that generates four alpha-particle emissions, was developed. A phase I trial demonstrated that 225Ac-lintuzumab is safe at doses of 3 μCi/kg or less and has antileukemic activity across all dose levels studied. Fractionated-dose 225Ac-lintuzumab in combination with low-dose cytarabine (LDAC) is now under investigation for the management of older patients with untreated AML in a multicenter trial. Preclinical studies using 213Bi- and astatine-211 (211At)-labeled anti-CD45 antibodies have shown that alpha-particle immunotherapy may be useful as part conditioning before hematopoietic cell transplantation. The use of novel pretargeting strategies may further improve target-to-normal organ dose ratios.

scholarly journals Aberrant expression of NKL homeobox genes HMX2 and HMX3 interferes with cell differentiation in acute myeloid leukemia

PLoS ONE ◽  
2020 ◽  
Vol 15 (10) ◽  
pp. e0240120
Author(s):  
Stefan Nagel ◽  
Claudia Pommerenke ◽  
Corinna Meyer ◽  
Roderick A. F. MacLeod ◽  
Hans G. Drexler
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Differentiation ◽  
Myeloid Leukemia ◽  
Homeobox Genes ◽  
Aberrant Expression ◽  
Acute Myeloid

Coagulopathy in HLA-DR Antigen-Negative Acute Myeloid Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4457-4457
Author(s):  
Hideki Uchiumi ◽  
Takafumi Matsushima ◽  
Arito Yamane ◽  
Hiroshi Handa ◽  
Hiroyuki Irisawa ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Myeloid Cell ◽  
Leukemic Cell ◽  
Leukemic Cells ◽  
Hla Dr ◽  
Risk Of Mortality ◽  
Acute Myeloid

Abstract Background: HLA-DR antigen is present on hematopoietic progenitors and granulocyte/monocyte, erythrocyte and megakaryocytic precursors but absent at the promyelocytic stage during myeloid cell maturation. In accordance with this, majority of promyelocytic leukemia (APL) cells were negative for HLA-DR. Meanwhile, some of non-APL acute myeloid leukemia (AML) cells is found to express HLA-DR. However, the clinical significance of HLA-DR antigen on AML cells is currently unclear. Purpose: We sought to determine the prevalence and clinical characteristics of negativity in HLA-DR expression by retrospectively analyzing 181 consecutive patients with de novo adult AML. Patients and Methods: AML patients examined in the current study (aged 15–86 years) had been diagnosed between August 1995 and July 2004, and categorized to M0 (8 patients), M1 (35), M2 (74), M3 (20), M4 (25), M5 (15), and M6 (4), based on the FAB classification. Median follow-up time was 19.3 months. Phenotypic analyses of leukemic cells were performed using CD45 gating methods. HLA-DR-negative AML was defined as HLA-DR expression less than 20% of cells in the CD45 leukemic cell gate. Results: Among 181 patients, HLA-DR antigens were not detected on AML cells from 46 patients; 20 with APL and 26 with non-APL (non-APL/DR(−)), the latter of which included M0 (2 patients), M1 (15), M2 (7), M4 (2). Leukemic cells from other non-APL patients were HLA-DR-positive (non-APL/DR(+)). None of non-APL/DR(−) patients had t(15;17) nor PML/RARa rearrangement on cytogenetic analysis. Twenty out of 26 patients with non-APL/DR(−) had normal chromosome, and 6 had abnormal karyotypes. In the non-APL/DR(−) group, various degrees of nuclear folding, convolution, or lobulation were observed in 9 patients. Although treatment response and overall survival rate were similar in the three groups (APL, non-APL/DR(−), and non-APL/DR(+)), both FDP levels at diagnosis (57.3 vs 13.2, p<0.05) and maximal FDP levels (232.6 vs 43.8, p<0.01) were significantly higher in non-APL/DR(−) compared with non-APL/DR(+). The maximal FDP levels in the non-APL/DR(−) patients were comparable to those in the APL patients. FDP levels greater than 40 mg/ml were significantly more prevalent in the non-APL/DR(−) than in the the non-APL/DR(−) group. Logistic regression analysis demonstrated that low HLA-DR expression was an independent risk factor for FDP > 40 mg/ml. Conclusion: Our study suggests that AML with negative HLA-DR antigen tend to be associated with abnormality in coagulation and fibrinolysis even if they are genetically non-APL. We propose that more attention should be paied for HLA-DR expression to avoid a devastating coagulopathy which carries a high risk of mortality unless specifically addressed.

c-myb Transactivates the Human Cyclin A1 Promoter and Induces Cyclin A1 Gene Expression

Blood ◽  
1999 ◽  
Vol 94 (12) ◽  
pp. 4255-4262 ◽  
Author(s):  
Carsten Müller ◽  
Rong Yang ◽  
Gregory Idos ◽  
Nicola Tidow ◽  
Sven Diederichs ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Expression Vector ◽  
Leukemia Cell ◽  
Myeloid Cell ◽  
Site Directed Mutagenesis ◽  
Cyclin A1 ◽  
High Level ◽  
Acute Myeloid

Cyclin A1 differs from other cyclins in its highly restricted expression pattern. Besides its expression during spermatogenesis, cyclin A1 is also expressed in hematopoietic progenitor cells and in acute myeloid leukemia. We investigated mechanisms that might contribute to cyclin A1 expression in hematopoietic cells. Comparison of cyclin A1 and cyclin A promoter activity in adherent and myeloid leukemia cell lines showed that the cyclin A1 promoter is preferentially active in myeloid cell lines. This preferential activity was present in a small, 335-bp cyclin A1 promoter fragment that contained several potential c-myb binding sites. Coexpression of a c-myb expression vector with the cyclin A1 promoter constructs significantly increased the reporter activity in adherent CV-1 as well as in myeloid U937 cells. Gel-shift assays demonstrated that c-myb could bind to the cyclin A1 promoter at a binding site located near the transcription start site. Site-directed mutagenesis of this site decreased promoter transactivation by 50% in both KCL22 cells that express high levels of c-myb and in CV-1 cells that were transfected with c-myb. In addition, transfection of primary human embryonic fibroblasts with a c-myb expression vector led to induction of the endogenous cyclin A1 gene. Taken together, c-myb can directly transactivate the promoter of cyclin A1, and c-myb might be involved in the high-level expression of cyclin A1 observed in acute myeloid leukemia. These findings suggest that c-myb induces hematopoiesis-specific mechanisms of cell cycle regulation.

The AF10 leucine zipper is required for leukemic transformation of myeloid progenitors by MLL-AF10

Blood ◽  
2002 ◽  
Vol 99 (10) ◽  
pp. 3780-3785 ◽  
Author(s):  
Jorge F. DiMartino ◽  
Paul M. Ayton ◽  
Everett H. Chen ◽  
Clarissa C. Naftzger ◽  
Bryan D. Young ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Amino Acid ◽  
Transcriptional Activation ◽  
Myeloid Leukemia ◽  
Leucine Zipper ◽  
Function Analysis ◽  
General Mechanism ◽  
Helical Domain ◽  
Acute Myeloid ◽  
Myeloid Progenitors

The t(10;11)(p12;q23) chromosomal translocation in human acute myeloid leukemia results in the fusion of theMLL and AF10 genes. The latter codes for a novel leucine zipper protein, one of many MLL fusion partners of unknown function. In this report, we demonstrate that retroviral-mediated transduction of an MLL-AF10complementary DNA into primary murine myeloid progenitors enhanced their clonogenic potential in serial replating assays and led to their efficient immortalization at a primitive stage of myeloid differentiation. Furthermore, MLL-AF10–transduced cells rapidly induced acute myeloid leukemia in syngeneic or severe combined immunodeficiency recipient mice. Structure/function analysis showed that a highly conserved 82–amino acid portion of AF10, comprising 2 adjacent α-helical domains, was sufficient for immortalizing activity when fused to MLL. Neither helical domain alone mediated immortalization, and deletion of the 29–amino acid leucine zipper within this region completely abrogated transforming activity. Similarly, the minimal oncogenic domain of AF10 exhibited transcriptional activation properties when fused to the MLL or GAL4 DNA-binding domains, while neither helical domain alone did. However, transcriptional activation per se was not sufficient because a second activation domain of AF10 was neither required nor competent for transformation. The requirement for α-helical transcriptional effector domains is similar to the oncogenic contributions of unrelated MLL partners ENL and ELL, suggesting a general mechanism of myeloid leukemogenesis by a subset of MLL fusion proteins, possibly through specific recruitment of the transcriptional machinery.

scholarly journals Homoharringtonine Synergized with Gilteritinib Results in the Downregulation of Myeloid Cell Leukemia-1 by Upregulating UBE2L6 in FLT3-ITD-Mutant Acute Myeloid (Leukemia) Cell Lines

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Jiayi Cai ◽  
Honghui Huang ◽  
Xiaoli Hu ◽  
Wenjing Lang ◽  
Wanbin Fu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Combination Therapy ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Myeloid Cell ◽  
Ubiquitin Proteasome System ◽  
Cell Leukemia ◽  
Ubiquitin Proteasome ◽  
Acute Myeloid

FMS-like tyrosine kinase 3 (FLT3) mutant acute myeloid leukemia (AML) occurs in approximately 30% of all AML patients and still has a poor prognosis. This study is directed to investigate gilteritinib in combination with homoharringtonine (HHT) on FLT3-ITD-mutant AML cell lines. In our study, we found that cell proliferation was dramatically suppressed by the combination of gilteritinib and HHT. This combination therapy decreased the mitochondrial membrane potential, finally inducing apoptosis. We demonstrated that gilteritinib downregulated the expression of FLT3 and downstream signaling, further decreased the mRNA level of myeloid cell leukemia-1 (Mcl-1). HHT and combination therapy could upregulate UBE2L6, which induced the degradation of Mcl-1 via ubiquitin-proteasome system. Knockdown of UBE2L6 could protect Mcl-1 from deprivation through the ubiquitin-proteasome system. These findings may provide a novel theoretical basis for the treatment of AML patients with FLT3-ITD mutations.

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