Persistence of multipotent progenitors expressing AML1/ETO transcripts in long-term remission patients with t(8;21) acute myelogenous leukemia

The leukemia-specific AML1/ETO fusion gene has been shown to be detected by reverse transcriptase polymerase chain reaction (RT-PCR) analysis in patients with t(8;21) acute myelogenous leukemia (AML) in long-term remission. In the present study, the AML1/ETO mRNA could be detected by RT-PCR in bone marrow (BM) and/or peripheral blood (PB) samples from all 18 patients who had been maintaining complete remission for 12 to 150 months (median, 45 months) following chemotherapy or PB stem cell transplantation (PBSCT), whereas it could not be detected in four patients who had been maintaining remission for more than 30 months following allogeneic BM transplantation (BMT). We surveyed the expression of AML1/ETO mRNA in clonogenic progenitors from BM in these cases. Notably, 51 of 2,469 colonies from clonogenic progenitors (2.1%) expressed the AML1/ETO mRNA in 18 cases who were RT- PCR+ in BM and/or PB samples. Expression was observed in various clonogenic progenitors, including granulocyte-macrophage colonies, mixed colonies, erythroid colonies, and megakaryocyte colonies. Furthermore, we analyzed the clonality of these progenitors by X- chromosome inactivation patterns of the phosphoglycerate kinase (PGK) gene in four female patients. The AML1/ETO mRNA+ progenitors showed the PGK allele identical to that detected in the leukemic blasts from the time of initial diagnosis. Normal constitutive hematopoiesis was sustained by polyclonal BM reconstitution in these patients. Accordingly, these committed progenitor cells that express AML1/ETO mRNA during remission likely have arisen from common t(8;21)+ pluripotent progenitor cells with at least trilineage differentiation potential. These data strongly suggest that the origin of the clonogenic leukemic progenitors of t(8;21) AML may be multipotent hematopoietic progenitors that acquired the t(8;21) chromosomal abnormality.

Download Full-text

Clinical Significance of AML/ETO Fusion Gene mRNA in Acute Myelogenous Leukemia.

Blood ◽

10.1182/blood.v104.11.4429.4429 ◽

2004 ◽

Vol 104 (11) ◽

pp. 4429-4429

Author(s):

Yungui Wang Master ◽

Jie Jin ◽

Zhimei Chen ◽

Yi Liang

Keyword(s):

Minimal Residual Disease ◽

Acute Myelogenous Leukemia ◽

De Novo ◽

Residual Disease ◽

Fusion Gene ◽

Western Country ◽

Myelogenous Leukemia ◽

Rt Pcr ◽

Acute Myelogenous ◽

Minimal Residual

Abstract Acute myelogenous leukemia (AML) patients with normal-karyotype may have undetected chromosome aberrant that could affect prognosis. Screening for known AML-specific genetic abnormalities using the reverse transcription polymerase chain reaction (RT-PCR) may help in arriving at a more definitive prognosis. And RT-PCR is the most sensitive method to detect Minimal residual disease (MRD). Nested PCR was a frequently used method to amplify AML1-ETO fusion gene. To further comprehend the relationship between AML1-ETO mRNA expression in AML and its clinical significance in Eastern China. We investigated the prevalence of t(8;21) (q22;q22) and AML1/ETO fusion gene in 461 unselected de novo patients with AML by single RT-PCR and compared the results of cytogenetic analysis with these of RT-PCR. The patients’ median age was 29(1–76). The results were used in diagnosis of 461 de novo leukemic patients, and 70 AML1-ETO-postive patients were followed up. 107 in 461 patients (23.2%) AML1/ETO was detected by RT-PCR. 98 in 461 patients (21.3%) showed t(8;21) (q22;q22) in karyotype analysis. All patients who had t(8;21) (q22;q22) in conventional karyotyping also showed the gene rearrangement in molecular analysis. The results showed that AML1/ETO mRNA could be expressed in cells from AML-M1, AML-M2 and AML-M4 patients. The complete remission rate in AML1/ETO-positive patients was significantly higher than that in AML1-ETO-negative patients (without M3 subtype patients)[80.4% (86/107) vs 70.6% (191/269)]. The AML1-ETO-postive patients who became negative after chemotherapy had an optimistic outcome, but the patients who demonstrated persistence of AML1-ETO mRNA had a poor prognosis. In chemotherapeutic group, patients whose AML1/ETO expression turning from negative (3 cases) or faint positive (1 case) to positive relapsed later. So PCR becoming positive again indicated relapsing. Only 7 was detected in 48 M2 t(8:21) patients who had been maintaining remission for more than 18 months. RT-PCR detected the overall AML1-ETO-positive rate in AML was from 6% to 13% in Western country. But our results showed the rate is 23.2%. One reason might be that the patients involved in our observation were younger than those patients involved in other observation group reported.. The other reason, which might be more important, was that the differences between China and Western country in race and region.Our results showed single RT-PCR method was sensitive enough to detect AML1-ETO mRNA. These observations suggest that AML1/ETO mRNA could disappear after chemotherapy or bone marrow transplantation. The patients had a great probability to relapse if the results of RT-PCR are continuously positive or change from negative to positive. So Regular detection is necessary for leukemia patients. We can monitor the minimal residual disease by detecting AML1-ETO mRNA regularly to direct clinical therapy

Download Full-text

Long-term Outcome of Autologous Transplantation of Peripheral Blood Progenitor Cells as Postremission Management of Patients ≥60 Years with Acute Myelogenous Leukemia

Biology of Blood and Marrow Transplantation ◽

10.1016/j.bbmt.2005.12.027 ◽

2006 ◽

Vol 12 (4) ◽

pp. 466-471 ◽

Cited By ~ 10

Author(s):

Ashkan Lashkari ◽

Tom Lowe ◽

Eric Collisson ◽

Ronald Paquette ◽

Christos Emmanouilides ◽

...

Keyword(s):

Progenitor Cells ◽

Peripheral Blood ◽

Acute Myelogenous Leukemia ◽

Autologous Transplantation ◽

Myelogenous Leukemia ◽

Term Outcome ◽

Long Term Outcome ◽

Peripheral Blood Progenitor Cells ◽

Acute Myelogenous

Download Full-text

Sesquiterpenoids from the roots of Inula helenium inhibit acute myelogenous leukemia progenitor cells

Bioorganic Chemistry ◽

10.1016/j.bioorg.2019.01.055 ◽

2019 ◽

Vol 86 ◽

pp. 363-367 ◽

Cited By ~ 3

Author(s):

Yahui Ding ◽

Wenwei Pan ◽

Junqing Xu ◽

Tianpeng Wang ◽

Tianyang Chen ◽

...

Keyword(s):

Progenitor Cells ◽

Acute Myelogenous Leukemia ◽

Myelogenous Leukemia ◽

Inula Helenium ◽

Acute Myelogenous

Download Full-text

144Outcome of hematopoietic progenitor cells transplant in patients with acute myelogenous leukemia in first complete remission report form a single institution

Biology of Blood and Marrow Transplantation ◽

10.1016/s1083-8791(03)80145-3 ◽

2003 ◽

Vol 9 (2) ◽

pp. 108

Author(s):

G.A. Milone ◽

J. Martinez Rolon ◽

I.I. Fernandez ◽

C.S. Corrado ◽

S. Pavlovsky ◽

...

Keyword(s):

Complete Remission ◽

Progenitor Cells ◽

Acute Myelogenous Leukemia ◽

Myelogenous Leukemia ◽

Hematopoietic Progenitor Cells ◽

Single Institution ◽

Hematopoietic Progenitor ◽

Acute Myelogenous ◽

First Complete Remission

Download Full-text

Detection and Characterization of Primitive Malignant and Normal Progenitors in Patients With Acute Myelogenous Leukemia Using Long-Term Coculture With Supportive Feeder Layers and Cytokines

Blood ◽

10.1182/blood.v90.7.2555 ◽

1997 ◽

Vol 90 (7) ◽

pp. 2555-2564 ◽

Cited By ~ 70

Author(s):

Laurie E. Ailles ◽

Brigitte Gerhard ◽

Donna E. Hogge

Keyword(s):

Acute Myelogenous Leukemia ◽

Culture Conditions ◽

Mouse Fibroblast ◽

Myelogenous Leukemia ◽

Leukemic Cells ◽

Information Culture ◽

Normal Individuals ◽

Exogenous Addition ◽

Acute Myelogenous

Abstract Analysis of the mitogenic activity of interleukin-3 (IL-3), Steel factor (SF ), and flt-3 ligand (FL) on acute myelogenous leukemia (AML) blasts using the short-term endpoints of proliferation in 3H-thymidine (3H-Tdr) incorporation assays or methylcellulose cultures (colony assays) showed that greater than 90% of samples contained cells that were responsive to one or more of these cytokines. With this information, culture conditions that were known to support normal long-term culture-initiating cells (LTC-IC) were tested, with or without supplements of one or more of these three growth factors, for their ability to support primitive progenitors from 10 cell samples from patients with AML. In all cases cytogenetically abnormal colony forming cells (CFC) were detected after 5 weeks when AML peripheral blood or marrow cells were cocultured on preestablished, normal human marrow feeders (HMF ) and/or Sl/Sl mouse fibroblast feeders and the number of CFC detected in these 5-week-old LTC maintained a linear relationship to the number of input AML cells. Limiting dilution analysis, performed on 6 of the 10 samples, showed the frequency of AML cells initiating LTC (AML LTC-IC) to be 5- to 300-fold lower than the frequency of AML-CFC in the same cell sample, whereas the average number of CFC produced per LTC-IC varied from 1 to 13. Surprisingly, in each case the concentration of cytogenetically normal LTC-IC detected in AML patient blood was at least 10-fold higher than that previously observed in the blood of normal individuals. “Mixed” mouse fibroblast feeders engineered to produce human G-CSF, IL-3, and SF did not enhance detection of AML LTC-IC but did increase the output of cytogenetically normal CFC from LTC of 3 of 4 patient samples. Supplementation of AML LTC with IL-3 and exogenously provided SF and/or FL increased the output of AML-CFC from 5-week-old LTC by greater than or equal to twofold with 5 of 9 patient samples, whereas in one case exogenous addition of FL reduced the output of malignant CFC from LTC. These studies show that conditions that support normal LTC-IC also allow a functionally analogous but rare AML progenitor cell type to be detected. In addition, differences in the responses of normal and leukemic cells to various cytokines active on normal LTC-IC were revealed. Further analysis of these differences may enhance our understanding of leukemogenesis and lead to observations that could be exploited therapeutically.

Download Full-text

Improved survival for patients with acute myelogenous leukemia.

Journal of Clinical Oncology ◽

10.1200/jco.1995.13.3.560 ◽

1995 ◽

Vol 13 (3) ◽

pp. 560-569 ◽

Cited By ~ 86

Author(s):

A J Mitus ◽

K B Miller ◽

D P Schenkein ◽

H F Ryan ◽

S K Parsons ◽

...

Keyword(s):

Overall Survival ◽

Acute Myelogenous Leukemia ◽

Myelogenous Leukemia ◽

Remission Induction ◽

Term Survival ◽

Free Survival ◽

Significant Difference ◽

Acute Myelogenous ◽

To Receive

PURPOSE Despite improvement in chemotherapy and supportive care over the past two decades, overall survival for patients with acute myelogenous leukemia (AML) remains poor; only 25% to 30% of individuals with this disorder will be cured. In 1987, we initiated a prospective multiinstitution study designed to improve long-term survival in adults with AML. METHODS We modified the usual 7-day treatment scheme of daunorubicin and cytarabine with high-dose cytarabine (HiDAC) on days 8 through 10 (3 + 7 + 3). Allogeneic or autologous bone marrow transplantation (BMT) was offered to all patients who entered complete remission (CR) to decrease the rate of leukemic relapse. Data were analyzed by intention to treat. RESULTS CRs were achieved in 84 of 94 patients (89%; 95% confidence interval [CI], 83 to 95). Because of the high remission rate, factors previously thought to predict outcome, such as cytogenetics, WBC count, French-American-British (FAB) classification, sex, and age, were not useful prognostic variables. The overall survival rate for the entire cohort of patients from data of diagnosis is 55% at 5 years. Sixty percent of all patients who achieved a CR underwent marrow grafting. There was no significant difference in event-free survival (EFS) at 5 years comparing patients assigned to receive allogeneic BMT with patients assigned to receive autologous BMT (56% v 45%, P = .54). CONCLUSION The long-term disease-free survival observed in this study is excellent compared with historical data. This improvement in survival is probably due to the high rate of remission induction, as well as to the effective nature of the consolidation therapy.

Download Full-text

Fusion of the Platelet-Derived Growth Factor Receptor β to a Novel Gene CEV14 in Acute Myelogenous Leukemia After Clonal Evolution

Blood ◽

10.1182/blood.v90.11.4271 ◽

1997 ◽

Vol 90 (11) ◽

pp. 4271-4277 ◽

Cited By ~ 84

Author(s):

Akihiro Abe ◽

Nobuhiko Emi ◽

Mitsune Tanimoto ◽

Hiroshi Terasaki ◽

Toru Marunouchi ◽

...

Keyword(s):

Growth Factor ◽

Acute Myelogenous Leukemia ◽

Fusion Gene ◽

Growth Factor Receptor ◽

Initial Diagnosis ◽

Myelogenous Leukemia ◽

Platelet Derived Growth Factor ◽

Novel Gene ◽

Wide Range ◽

Acute Myelogenous

Abstract Chromosomal translocations involving band 5q31-35 occur in several hematologic disorders. A clone with a t(5; 14)(q33; q32) translocation appeared at the relapse phase in a patient with acute myelogenous leukemia who exhibited a sole chromosomal translocation, t(7; 11), at initial diagnosis. After the appearance of this clone, the leukemia progressed with marked eosinophilia, and combination chemotherapy was ineffective. Southern blot analysis showed a rearrangement of the platelet-derived growth factor receptor β (PDGFRβ) gene at 5q33 which was not observed at initial diagnosis. This translocation resulted in a chimeric transcript fusing the PDGFRβ gene on 5q33 with a novel gene, CEV14, located at 14q32. Expression of the 5′ region of the PDGFRβ cDNA, upstream of the breakpoint, was not detected. However, the 3′ region of PDGFRβ, which was transcribed as part of the CEV14-PDGFRβ fusion gene, was detected. A partial cDNA for a novel gene, CEV14, includes a leucine zipper motif and putative thyroid hormone receptor interacting domain and is expressed in a wide range of tissues. The expression of a CEV14-PDGFRβ fusion gene in association with aggressive leukemia progression suggests that this protein has oncogenic potential.

Download Full-text

High-risk acute myelogenous leukemia: treatment today … and tomorrow

Hematology ◽

10.1182/asheducation-2013.1.201 ◽

2013 ◽

Vol 2013 (1) ◽

pp. 201-208 ◽

Cited By ~ 15

Author(s):

Gary J. Schiller

Keyword(s):

High Risk ◽

Acute Myelogenous Leukemia ◽

Poor Response ◽

Myelogenous Leukemia ◽

Term Survival ◽

Long Term Survival ◽

Clinical Variables ◽

Molecular Abnormalities ◽

Acute Myelogenous

Abstract High-risk acute myelogenous leukemia (AML) constitutes a distinct subset of disease based on clinical and biological characteristics and comprises a significant percentage of all cases of adult AML. Biologic features such as distinct clonal cytogenetic and molecular abnormalities identify a subgroup of AML patients characterized by poor response to induction chemotherapy and poor long-term survival after treatment with consolidation chemotherapy. Clinical variables that predict for poor response include AML relapsed after less than 1 year of remission and AML characterized by resistance to conventional agents. We review here our understanding of the defining biologic subtypes of AML and discuss how adequate initial evaluation can be used to inform the choice of treatment. By defining high-risk biologic and clinical variables, a strong case can be made for treating patients with investigational agents, with treatment directed at distinct cytogenetic or molecular abnormalities. Allogeneic transplantation is the only form of therapy available outside of the setting of a clinical trial that may offer a chance for long-term survival for patients with high-risk AML.

Download Full-text