scholarly journals Intermittent Exposure of Primitive Quiescent Chronic Myeloid Leukemia Cells to Granulocyte-Colony Stimulating Factor In vitro Promotes their Elimination by Imatinib Mesylate

2006 ◽  
Vol 12 (2) ◽  
pp. 626-633 ◽  
Author(s):  
Heather G. Jørgensen ◽  
Mhairi Copland ◽  
Elaine K. Allan ◽  
Xiaoyan Jiang ◽  
Allen Eaves ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Imatinib Mesylate ◽  
Myeloid Leukemia ◽  
Leukemia Cells ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Intermittent Exposure ◽  
Stimulating Factor

scholarly journals Effect of human recombinant granulocyte colony-stimulating factor on induction of myeloid leukemias by X-irradiation in mice

Blood ◽  
1993 ◽  
Vol 82 (7) ◽  
pp. 2163-2168 ◽  
Author(s):  
Y Kawase ◽  
M Akashi ◽  
H Ohtsu ◽  
Y Aoki ◽  
A Akanuma ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Whole Body ◽  
Leukemia Cells ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Myeloid Leukemias ◽  
Fab Classification ◽  
Radiation Induced ◽  
Stimulating Factor

Hematopoietic suppression is one of the serious problems induced by whole body irradiation. Granulocyte colony-stimulating factor (G-CSF) stimulates the progenitors of granulocytes and accelerates their recovery from bone marrow suppression induced by cytotoxic chemotherapy or radiation. On the other hand, G-CSF stimulates proliferation of myeloid leukemia cells as well as normal granulocytes in vitro. We designed a method to determine if G-CSF affects the incidence of myeloid leukemias induced by irradiation and the types of leukemias induced according to the French-American-British (FAB) classification in RFM/MsNrs mice. Administration of G-CSF (2 micrograms/d for 7 days) after a single 3-Gy irradiation significantly increased the number of peripheral blood neutrophils as compared with those in control mice. Even after discontinuation of G-CSF, both the total leukocyte and neutrophil counts increased to day 10, and their levels remained elevated until day 14. The incidence of myeloid leukemia in mice exposed to a single 3-Gy irradiation was 18.6% (38 of 204), and treatment with G-CSF did not increase the incidence (15.7% [32 of 204]). In the mice with radiation-induced leukemia, those receiving G- CSF had a mean survival time of 357 days, whereas those not receiving the factor survived for 349 days. There was no significant difference of survivals between the two groups. Most of the radiation-induced leukemias in the two groups were M1 or M2, according to the FAB classification; no characteristic difference was observed among the types of leukemias. Although G-CSF stimulated the leukemia cells in vitro, G-CSF administration after irradiation did not increase the occurrence of radiation-induced myeloid leukemias. Our results show that administration of G-CSF effectively accelerates neutrophil recovery from irradiation-induced hematopoietic injury and does not enhance the induction of myeloid leukemia in RFM/MsNrs mice by irradiation.

scholarly journals Effect of human recombinant granulocyte colony-stimulating factor on induction of myeloid leukemias by X-irradiation in mice

Blood ◽  
1993 ◽  
Vol 82 (7) ◽  
pp. 2163-2168 ◽  
Author(s):  
Y Kawase ◽  
M Akashi ◽  
H Ohtsu ◽  
Y Aoki ◽  
A Akanuma ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Whole Body ◽  
Leukemia Cells ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Myeloid Leukemias ◽  
Fab Classification ◽  
Radiation Induced ◽  
Stimulating Factor

Abstract Hematopoietic suppression is one of the serious problems induced by whole body irradiation. Granulocyte colony-stimulating factor (G-CSF) stimulates the progenitors of granulocytes and accelerates their recovery from bone marrow suppression induced by cytotoxic chemotherapy or radiation. On the other hand, G-CSF stimulates proliferation of myeloid leukemia cells as well as normal granulocytes in vitro. We designed a method to determine if G-CSF affects the incidence of myeloid leukemias induced by irradiation and the types of leukemias induced according to the French-American-British (FAB) classification in RFM/MsNrs mice. Administration of G-CSF (2 micrograms/d for 7 days) after a single 3-Gy irradiation significantly increased the number of peripheral blood neutrophils as compared with those in control mice. Even after discontinuation of G-CSF, both the total leukocyte and neutrophil counts increased to day 10, and their levels remained elevated until day 14. The incidence of myeloid leukemia in mice exposed to a single 3-Gy irradiation was 18.6% (38 of 204), and treatment with G-CSF did not increase the incidence (15.7% [32 of 204]). In the mice with radiation-induced leukemia, those receiving G- CSF had a mean survival time of 357 days, whereas those not receiving the factor survived for 349 days. There was no significant difference of survivals between the two groups. Most of the radiation-induced leukemias in the two groups were M1 or M2, according to the FAB classification; no characteristic difference was observed among the types of leukemias. Although G-CSF stimulated the leukemia cells in vitro, G-CSF administration after irradiation did not increase the occurrence of radiation-induced myeloid leukemias. Our results show that administration of G-CSF effectively accelerates neutrophil recovery from irradiation-induced hematopoietic injury and does not enhance the induction of myeloid leukemia in RFM/MsNrs mice by irradiation.

scholarly journals Truncated RUNX1 Generated by the Fusion of RUNX1 to Antisense GRIK2 via a Cryptic Chromosome Translocation Enhances Sensitivity to Granulocyte Colony-Stimulating Factor

2020 ◽  
Vol 160 (5) ◽  
pp. 255-263 ◽  
Author(s):  
Akihiro Abe ◽  
Yukiya Yamamoto ◽  
Akira Katsumi ◽  
Hideyuki Yamamoto ◽  
Akinao Okamoto ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Chromosomal Abnormalities ◽  
Chromosome Translocation ◽  
Leukemia Cells ◽  
Antisense Strand ◽  
Fusion Partner ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Hematological Disorders ◽  
Stimulating Factor

Fusions of the Runt-related transcription factor 1 (RUNX1) with different partner genes have been associated with various hematological disorders. Interestingly, the C-terminally truncated form of RUNX1 and RUNX1 fusion proteins are similarly considered important contributors to leukemogenesis. Here, we describe a 59-year-old male patient who was initially diagnosed with acute myeloid leukemia, inv(16)(p13;q22)/CBFB-MYH11 (FAB classification M4Eo). He achieved complete remission and negative CBFB-MYH11 status with daunorubicin/cytarabine combination chemotherapy but relapsed 3 years later. Cytogenetic analysis of relapsed leukemia cells revealed CBFB-MYH11 negativity and complex chromosomal abnormalities without inv(16)(p13;q22). RNA-seq identified the glutamate receptor, ionotropic, kinase 2 (GRIK2) gene on 6q16 as a novel fusion partner for RUNX1 in this case. Specifically, the fusion of RUNX1 to the GRIK2 antisense strand (RUNX1-GRIK2as) generated multiple missplicing transcripts. Because extremely low levels of wild-type GRIK2 were detected in leukemia cells, RUNX1-GRIK2as was thought to drive the pathogenesis associated with the RUNX1-GRIK2 fusion. The truncated RUNX1 generated from RUNX1-GRIK2as induced the expression of the granulocyte colony-stimulating factor (G-CSF) receptor on 32D myeloid leukemia cells and enhanced proliferation in response to G-CSF. In summary, the RUNX1-GRIK2as fusion emphasizes the importance of aberrantly truncated RUNX1 in leukemogenesis.

scholarly journals Selective Expansion of Primitive Normal Hematopoietic Cells in Cytokine-Supplemented Cultures of Purified Cells From Patients With Chronic Myeloid Leukemia

Blood ◽  
1997 ◽  
Vol 90 (1) ◽  
pp. 64-69 ◽  
Author(s):  
A.L. Petzer ◽  
C.J. Eaves ◽  
M.J. Barnett ◽  
A.C. Eaves
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Hematopoietic Cells ◽  
Granulocyte Colony Stimulating Factor ◽  
Flt3 Ligand ◽  
Stem Cell Rescue ◽  
In Vitro Expansion ◽  
Stimulating Factor

We have previously reported that primitive normal hematopoietic cells detectable as long-term culture-initiating cells (Ph-LTC-IC) are present at high levels in the blood of some patients with chronic myeloid leukemia (CML). We now show that this population can be expanded several-fold when highly purified CD34+CD38− cells isolated from the blood of such patients are cultured for 10 days in a serum-free medium containing 100 ng/mL of Flt3-ligand and Steel factor and 20 ng/mL of interleukin-3 (IL-3) and IL-6, and granulocyte colony-stimulating factor. In similar cultures initiated with CD34+CD38− cells from CML blood samples in which all of the LTC-IC were leukemic (Ph+), Ph+ LTC-IC activity was rapidly lost both in the presence and absence of admixed CD34+CD38− cells isolated from normal marrow. Conversely, the ability of normal LTC-IC to expand their numbers was shown to be independent of the presence of Ph+LTC-IC and later types of Ph+colony-forming cell (CFC) progenitors. In contrast to the LTC-IC, CFC were consistently -a m p l i f i e d  i n  c u l t u r e s  i n i t i a t e d  w i t h  C M L - d e r i v e d -CD34+CD38− cells and the additional CFC present after 10 days were, like the starting population of CFC, almost exclusively Ph+ regardless of the genotype(s) of the LTC-IC in the original CML samples. Amplification of the Ph+CFC population in these cultures showed the same factor dependence as previously demonstrated for the in vitro expansion of CFC from normal marrow CD34+CD38− cells. Ph+LTC-IC disappeared regardless of the cytokines present. Taken together these findings support a model of CML in which the leukemic stem cells are characterized by a decreased probability of self-renewal and an increased probability of differentiation. In addition, they suggest new opportunities for improving the treatment of CML using strategies that require autologous stem cell rescue.

Upregulation of hGC-1 Expression by Hypomethylation, Retinoic Acid and Interferons in Human Myeloid Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4486-4486
Author(s):  
Wenli Liu ◽  
Griffin P Rodgers
Keyword(s):  
Retinoic Acid ◽  
Myeloid Leukemia ◽  
Target Gene ◽  
Leukemia Cells ◽  
Luciferase Reporter ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Response Element ◽  
Gene Assay ◽  
Stimulating Factor

Abstract hGC-1 (Granulocyte colony stimulating factor induced gene-1, also called GW112 and olfactomedin 4) was first identified in human myeloid precursor cells induced by granulocyte colony stimulating factor (G-CSF). It is a myeloid lineage and differentiation stage specific gene. Its expression, regulation and biological function, specifically in myeloid cells, are still poorly understood. In this study, we analyzed the hGC-1 gene expression in leukemia patients and further investigated the mechanism of hGC-1 gene regulation in leukemia cells. We found that hGC-1 was overexpressed in myeloid leukemia patients compared with normal individuals in peripheral blood leukocytes (p<0.01) and its expression in accelerated phase of chronic myeloid leukemia (CML) patients was significantly higher than that in chronic phase (p<0.01) using a dot blot and quantitative RT-PCR analysis. Hypomethylation of CpG sites in the promoter of hGC-1 gene were observed in CML patients by pyrosequence and 5-aza-2′-deoxycytidine induced hGC-1 expression in myeloid leukemia cells, suggesting that promoter CpG methylation status affects the expression of hGC-1 gene. All-trans-retinoic acid (ATRA) and interferons (IFNs) are active anti-leukemia agents. ATRA and IFNs have shown synergistic interactions in various experimental conditions and represent a potentially useful therapeutic combination in the treatment of various types of leukemia. However, the target genes and molecular basis of these interactions still needs to be further elucidated. Here, we identified that hGC-1 was a target gene of RA in myeloblastic leukemia cells. Treatment with ATRA induced hGC-1 expression in HL-60 cells and enhanced hGC-1 expression in AML-193 and GDM-1 cells. Deletion analysis led to the identification of a positive retinoic acid response element (DR5) and a negative response element (DR1) within hGC-1 promoter. Furthermore, electrophoretic mobility-shift assays demonstrated that RARa/RXRa binds to the DR5 site. Transfection study in COS-7 cells revealed RARa/RXRa mediated the RA induced transactivation of hGC-1 promoter. We also found that hGC-1 was an early responsive gene of IFN a and b in myeloid leukemia cells (HL-60, AML-193 and GDM-1). An effective interferon-stimulated response element (ISRE) was identified in the promoter of hGC-1 gene by examining the deletion mutants in luciferase reporter gene assay. Combined application of ATRA and IFNa and IFNb enhanced hGC-1 expression synergistically. Taken together, hGC-1 is identified as a novel target gene of methylation modification, RA and IFNs in myeloid leukemia cells. Our results suggest that hGC-1 is a potential marker for CML stage and may play a role in retinoic acid and interferon induced biological effects in leukemia cells.

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