scholarly journals Stem Cell Modeling of Core Binding Factor Acute Myeloid Leukemia

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Federico Mosna ◽  
Michele Gottardi
Keyword(s):  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Chromosomal Abnormalities ◽  
Core Binding Factor ◽  
Hematopoietic Stem ◽  
Cell Modeling ◽  
Binding Factor ◽  
Acute Myeloid

Even though clonally originated from a single cell, acute leukemia loses its homogeneity soon and presents at clinical diagnosis as a hierarchy of cells endowed with different functions, of which only a minority possesses the ability to recapitulate the disease. Due to their analogy to hematopoietic stem cells, these cells have been named “leukemia stem cells,” and are thought to be chiefly responsible for disease relapse and ultimate survival after chemotherapy. Core Binding Factor (CBF) Acute Myeloid Leukemia (AML) is cytogenetically characterized by either the t(8;21) or the inv(16)/t(16;16) chromosomal abnormalities, which, although being pathognomonic, are not sufficientper seto induce overt leukemia but rather determine a preclinical phase of disease when preleukemic subclones compete until the acquisition of clonal dominance by one of them. In this review we summarize the concepts regarding the application of the “leukemia stem cell” theory to the development of CBF AML; we will analyze the studies investigating the leukemogenetic role of t(8;21) and inv(16)/t(16;16), the proposed theories of its clonal evolution, and the role played by the hematopoietic niches in preserving the disease. Finally, we will discuss the clinical implications of stem cell modeling of CBF AML for the therapy of the disease.

KIT Exon 8 Mutations Associated with Core Binding Factor (CBF) - Acute Myeloid Leukemia (AML) Cause Hypersensitivity of KIT to Its Natural Ligand Stem Cell Factor.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 92-92
Author(s):  
Tobias M. Kohl ◽  
Susanne Schnittger ◽  
Wolfgang Hiddemann ◽  
Karsten Spiekermann
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Stem Cell Factor ◽  
Myeloid Leukemia ◽  
Biological Effects ◽  
Nucleotide Sequencing ◽  
Core Binding Factor ◽  
Binding Factor ◽  
Significant Difference ◽  
Acute Myeloid

Abstract Mutations in the extracellular portion of the KIT receptor tyrosine kinase (exon 8 mutations) are strongly associated with core binding factor (CBF) - acute myeloid leukemia (AML), but the functional role of these mutations has not been elucidated. In 93% of cases, codon Asp419 is deleted and exon 8 mutations were reported to confer an impaired prognosis to patients with CBF-AML. In this study, we are the first to report pro-proliferative and antiapoptotic potential of representative KIT exon 8 mutations in a cell culture model and to show a significant difference to KIT wildtype (KIT-WT). Three representative exon 8 mutants including a single deletion of codon 419 were created by in vitro site-directed mutagenesis. The integrity of all constructs was assessed by complete nucleotide sequencing. After stable expression in IL-3 dependent Ba/F3 cells (confirmed by FACS analysis and immunoblotting), exon 8 KIT mutants were characterized by a hypersensitivity to stem cell factor (SCF) stimulation in terms of proliferation and resistance to apoptotic cell death. The differences to KIT-WT occurred in the physiological range of SCF from 1 to 10ng/ml. The proliferative response caused by stimulation with SCF was reversed in KIT-WT and exon 8 mutants in the presence of Imatinib® (Novartis) in contrast to the activation loop mutant D816V which could not be inhibited. These biological effects were confirmed by demonstrating increased phosphorylation of the KIT downstream targets mitogen-activated protein kinase (MAPK) and AKT after SCF stimulation compared to the KIT-WT receptor. Furthermore, the MEK inhibitor PD98059 and the PI3 kinase inhibitor LY294002 resulted in a dose dependent inhibition of SCF induced proliferation in exon 8 mutants. Our data show that KIT exon 8 mutations represent gain-of-function mutations by inducing receptor hypersensitivity to its ligand SCF by activation of MAPK and PI3K and might represent a new molecular target for treatment of CBF leukemias.

KIT exon 8 mutations associated with core-binding factor (CBF)–acute myeloid leukemia (AML) cause hyperactivation of the receptor in response to stem cell factor

Blood ◽  
2005 ◽  
Vol 105 (8) ◽  
pp. 3319-3321 ◽  
Author(s):  
Tobias M. Kohl ◽  
Susanne Schnittger ◽  
Joachim W. Ellwart ◽  
Wolfgang Hiddemann ◽  
Karsten Spiekermann
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Stem Cell Factor ◽  
Myeloid Leukemia ◽  
Apoptotic Cell ◽  
Mitogen Activated Protein Kinase ◽  
Core Binding Factor ◽  
Binding Factor ◽  
Mitogen Activated Protein ◽  
Acute Myeloid

AbstractKIT exon 8 mutations are located in the extracellular portion of the receptor and are strongly associated with core-binding factor (CBF)-acute myeloid leukemia (AML). To characterize the functional role of these mutants, we analyzed the proproliferative and antiapoptotic potential of 3 KIT exon 8 mutations in interleukin 3 (IL-3)-dependent Ba/F3 cells. All KIT exon 8 mutants induced receptor hyperactivation in response to stem cell factor (SCF) stimulation in terms of proliferation and resistance toward apoptotic cell death. A representative KIT exon 8 mutant showed spontaneous receptor dimerization, phosphorylation of mitogen-activated protein kinase (MAPK), and conferred IL-3-independent growth to Ba/F3 cells. MAPK and phosphatidylinositol 3-kinase (PI3-kinase) activation was essential for the phenotype of this mutant. Additionally, imatinib inhibited proliferation of KIT exon 8 mutant-expressing Ba/F3 cells. Our data show that KIT exon 8 mutations represent gain-of-function mutations and might represent a new molecular target for treatment of CBF leukemias. (Blood. 2005;105:3319-3321)

scholarly journals CXCR4 Antagonists as Stem Cell Mobilizers and Therapy Sensitizers for Acute Myeloid Leukemia and Glioblastoma?

Biology ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 31 ◽  
Author(s):  
Vashendriya V.V. Hira ◽  
Cornelis J.F. Van Noorden ◽  
Remco J. Molenaar
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Patient Survival ◽  
Hematopoietic Stem ◽  
Poor Patient ◽  
Acute Myeloid ◽  
Poor Patient Survival

Glioblastoma is the most aggressive and malignant primary brain tumor in adults and has a poor patient survival of only 20 months after diagnosis. This poor patient survival is at least partly caused by glioblastoma stem cells (GSCs), which are slowly-dividing and therefore therapy-resistant. GSCs are localized in protective hypoxic peri-arteriolar niches where these aforementioned stemness properties are maintained. We previously showed that hypoxic peri-arteriolar GSC niches in human glioblastoma are functionally similar to hypoxic peri-arteriolar hematopoietic stem cell (HSC) niches in human bone marrow. GSCs and HSCs express the receptor C-X-C receptor type 4 (CXCR4), which binds to the chemoattractant stromal-derived factor-1α (SDF-1α), which is highly expressed in GSC niches in glioblastoma and HSC niches in bone marrow. This receptor–ligand interaction retains the GSCs/HSCs in their niches and thereby maintains their slowly-dividing state. In acute myeloid leukemia (AML), leukemic cells use the SDF-1α–CXCR4 interaction to migrate to HSC niches and become slowly-dividing and therapy-resistant leukemic stem cells (LSCs). In this communication, we aim to elucidate how disruption of the SDF-1α–CXCR4 interaction using the FDA-approved CXCR4 inhibitor plerixafor (AMD3100) may be used to force slowly-dividing cancer stem cells out of their niches in glioblastoma and AML. Ultimately, this strategy aims to induce GSC and LSC differentiation and their sensitization to therapy.

Evi-1 is a transcriptional target of mixed-lineage leukemia oncoproteins in hematopoietic stem cells

Blood ◽  
2011 ◽  
Vol 117 (23) ◽  
pp. 6304-6314 ◽  
Author(s):  
Shunya Arai ◽  
Akihide Yoshimi ◽  
Munetake Shimabe ◽  
Motoshi Ichikawa ◽  
Masahiro Nakagawa ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Myeloid Leukemia ◽  
Mixed Lineage Leukemia ◽  
Aberrant Expression ◽  
Hematopoietic Stem ◽  
Acute Myeloid

Abstract Ecotropic viral integration site-1 (Evi-1) is a nuclear transcription factor that plays an essential role in the regulation of hematopoietic stem cells. Aberrant expression of Evi-1 has been reported in up to 10% of patients with acute myeloid leukemia and is a diagnostic marker that predicts a poor outcome. Although chromosomal rearrangement involving the Evi-1 gene is one of the major causes of Evi-1 activation, overexpression of Evi-1 is detected in a subgroup of acute myeloid leukemia patients without any chromosomal abnormalities, which indicates the presence of other mechanisms for Evi-1 activation. In this study, we found that Evi-1 is frequently up-regulated in bone marrow cells transformed by the mixed-lineage leukemia (MLL) chimeric genes MLL-ENL or MLL-AF9. Analysis of the Evi-1 gene promoter region revealed that MLL-ENL activates transcription of Evi-1. MLL-ENL–mediated up-regulation of Evi-1 occurs exclusively in the undifferentiated hematopoietic population, in which Evi-1 particularly contributes to the propagation of MLL-ENL–immortalized cells. Furthermore, gene-expression analysis of human acute myeloid leukemia cases demonstrated the stem cell–like gene-expression signature of MLL-rearranged leukemia with high levels of Evi-1. Our findings indicate that Evi-1 is one of the targets of MLL oncoproteins and is selectively activated in hematopoietic stem cell–derived MLL leukemic cells.

Hematopoietic stem cell transplantation for core binding factor acute myeloid leukemia: t(8;21) and inv(16) represent different clinical outcomes

Blood ◽  
2009 ◽  
Vol 113 (9) ◽  
pp. 2096-2103 ◽  
Author(s):  
Yachiyo Kuwatsuka ◽  
Koichi Miyamura ◽  
Ritsuro Suzuki ◽  
Masaharu Kasai ◽  
Atsuo Maruta ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Myeloid Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Prospective Trial ◽  
Hematopoietic Stem ◽  
Binding Factor ◽  
Acute Myeloid

We analyzed 338 adult patients with acute myeloid leukemia (AML) with t(8;21) and inv(16) undergoing stem cell transplantation (SCT) who were registered in the Japan Society for Hematopoietic Cell Transplantation database. At 3 years, overall survival (OS) of patients with t(8;21) and inv(16) was 50% and 72%, respectively (P = .002). Although no difference was observed when restricted to allogeneic SCT in first complete remission (CR; 84% and 74%), OS of patients with t(8;21) and inv(16) undergoing allogeneic SCT in second or third CR (45% and 86% at 3 years; P = .008) was different. OS was not different between patients in first CR who received allogeneic SCT and those who received autologous SCT for both t(8;21) AML (84% vs 77%; P = .49) and inv(16) AML (74% vs 59%; P = .86). Patients with inv(16) not in CR did better after allogeneic SCT than those with t(8;21) (70% and 18%; P = .03). Patients with t(8;21) and inv(16) should be managed differently as to the application of SCT. SCT in first CR is not necessarily recommended for inv(16). For t(8;21) patients in first CR, a prospective trial is needed to clarify the significance of autologous SCT and allogeneic SCT over chemotherapy.

Results of Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia of the FAB M0 Subtype in First Complete Remission: A Survey of the Acute Leukemia Working Party of the European Bone Marrow Transplant Group (EBMT).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5131-5131
Author(s):  
Andree-Laure Herr ◽  
Myriam Labopin ◽  
Rosy Reiffers ◽  
Donald Bunjes ◽  
Didier Blaise ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Hematopoietic Stem ◽  
First Complete Remission ◽  
Acute Myeloid

Abstract Hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for patients with acute myeloid leukemia (AML). AML of the FAB M0 subtype is rare, often associated with a complex karyotype and a poor prognosis. Results of HSCT for this AML subtype have never been reported separately from other subtypes. We did a survey of the results of 274 HSCT in adults with M0 AML in first complete remission (CR1), performed in EBMT centres since January 1990 until 2002. One hundred fifty patients were transplanted with an HLA identical donor (HLA-id), 30 with an HLA-matched unrelated donor (MUD) and 94 received an autologous transplant (auto). The median age was 45 years (16–71), the median interval from diagnosis to HSCT was 4 months for HLA-id, 6 months for MUD and 5 months for auto HSCT. The median follow-up time (range) was 20 months (1–109), 12 (2–53) and 10 months (1–96) for HLA-id, MUD and auto-HSCT respectively. The source of stem cells was peripheral blood stem cells for 67% of cases, and bone marrow for the remaining. The majority of grafts were non-T-cell depleted. Acute GVHD (grade I–IV) occurred in 56% of HLA-id and in 64% of MUD cases. The table shows the outcomes at two years according to the type of transplant. In conclusion, outcomes after HLA identical HSCT and MUD in adult patients with AML FAB subtype M0 in CR1 are encouraging. In comparison to allogeneic transplant cases, LFS is decreased in patients receiving an autologous transplant due to a high relapse incidence, reflecting the probable role of a graft-versus-leukemia effect in this FAB subtype. Results of HSCT in AML M0 CR1 patients Outcomes HLA-id n=150 MUD n= 30 Auto n=94 LFS: leukemia free survival; OS: overall survival; RI: relapse incidence; TRM: treatment-related mortality 2y LFS 50% 45% 33% 2y OS 58% 50% 49% 2y RI 25% 40% 57% 2y TRM 24% 14% 9%

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