CD34+ Acute Myeloid and Lymphoid Leukemic Blasts Can Be Induced to Differentiate Into Dendritic Cells

Blood ◽  
1999 ◽  
Vol 94 (6) ◽  
pp. 2048-2055
Author(s):  
A. Cignetti ◽  
E. Bryant ◽  
B. Allione ◽  
A. Vitale ◽  
R. Foa ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Myelogenous Leukemia ◽  
Chromosome 7 ◽  
Leukemic Cells ◽  
Interleukin 4 ◽  
Hematopoietic Stem ◽  
Acute Myeloid

CD34+ hematopoietic stem cells from normal individuals and from patients with chronic myelogenous leukemia can be induced to differentiate into dendritic cells (DC). The aim of the current study was to determine whether acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) cells could be induced to differentiate into DC. CD34+ AML-M2 cells with chromosome 7 monosomy were cultured in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor  (TNF), and interleukin-4 (IL-4). After 3 weeks of culture, 35% of the AML-M2 cells showed DC morphology and phenotype. The DC phenotype was defined as upmodulation of the costimulatory molecules CD80 and CD86 and the expression of CD1a or CD83. The leukemic nature of the DC was validated by detection of chromosome 7 monosomy in sorted DC populations by fluorescence in situ hybridization (FISH). CD34+ leukemic cells from 2 B-ALL patients with the Philadelphia chromosome were similarly cultured, but in the presence of CD40-ligand and IL-4. After 4 days of culture, more than 58% of the ALL cells showed DC morphology and phenotype. The leukemic nature of the DC was validated by detection of the bcr-abl fusion gene in sorted DC populations by FISH. In functional studies, the leukemic DC were highly superior to the parental leukemic blasts for inducing allogeneic T-cell responses. Thus, CD34+ AML and ALL cells can be induced to differentiate into leukemic DC with morphologic, phenotypic, and functional similarities to normal DC.

CD34+ Acute Myeloid and Lymphoid Leukemic Blasts Can Be Induced to Differentiate Into Dendritic Cells

Blood ◽  
1999 ◽  
Vol 94 (6) ◽  
pp. 2048-2055 ◽  
Author(s):  
A. Cignetti ◽  
E. Bryant ◽  
B. Allione ◽  
A. Vitale ◽  
R. Foa ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Myelogenous Leukemia ◽  
Chromosome 7 ◽  
Leukemic Cells ◽  
Interleukin 4 ◽  
Hematopoietic Stem ◽  
Acute Myeloid

Abstract CD34+ hematopoietic stem cells from normal individuals and from patients with chronic myelogenous leukemia can be induced to differentiate into dendritic cells (DC). The aim of the current study was to determine whether acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) cells could be induced to differentiate into DC. CD34+ AML-M2 cells with chromosome 7 monosomy were cultured in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor  (TNF), and interleukin-4 (IL-4). After 3 weeks of culture, 35% of the AML-M2 cells showed DC morphology and phenotype. The DC phenotype was defined as upmodulation of the costimulatory molecules CD80 and CD86 and the expression of CD1a or CD83. The leukemic nature of the DC was validated by detection of chromosome 7 monosomy in sorted DC populations by fluorescence in situ hybridization (FISH). CD34+ leukemic cells from 2 B-ALL patients with the Philadelphia chromosome were similarly cultured, but in the presence of CD40-ligand and IL-4. After 4 days of culture, more than 58% of the ALL cells showed DC morphology and phenotype. The leukemic nature of the DC was validated by detection of the bcr-abl fusion gene in sorted DC populations by FISH. In functional studies, the leukemic DC were highly superior to the parental leukemic blasts for inducing allogeneic T-cell responses. Thus, CD34+ AML and ALL cells can be induced to differentiate into leukemic DC with morphologic, phenotypic, and functional similarities to normal DC.

Identification of human chronic myelogenous leukemia progenitor cells with hemangioblastic characteristics

Blood ◽  
2005 ◽  
Vol 105 (7) ◽  
pp. 2733-2740 ◽  
Author(s):  
Baijun Fang ◽  
Chunmei Zheng ◽  
Lianming Liao ◽  
Qin Han ◽  
Zhao Sun ◽  
...  
Keyword(s):  
Stem Cells ◽  
Endothelial Cells ◽  
Progenitor Cells ◽  
Chronic Myelogenous Leukemia ◽  
Blood Cells ◽  
Fusion Gene ◽  
Fetal Liver ◽  
Philadelphia Chromosome ◽  
Myelogenous Leukemia ◽  
Leukemic Cells

AbstractOverwhelming evidence from leukemia research has shown that the clonal population of neoplastic cells exhibits marked heterogeneity with respect to proliferation and differentiation. There are rare stem cells within the leukemic population that possess extensive proliferation and self-renewal capacity not found in the majority of the leukemic cells. These leukemic stem cells are necessary and sufficient to maintain the leukemia. Interestingly, the BCR/ABL fusion gene, which is present in chronic myelogenous leukemia (CML), was also detected in the endothelial cells of patients with CML, suggesting that CML might originate from hemangioblastic progenitor cells that can give rise to both blood cells and endothelial cells. Here we isolated fetal liver kinase-1–positive (Flk1+) cells carrying the BCR/ABL fusion gene from the bone marrow of 17 Philadelphia chromosome–positive (Ph+) patients with CML and found that these cells could differentiate into malignant blood cells and phenotypically defined endothelial cells at the single-cell level. These findings provide direct evidence for the first time that rearrangement of the BCR/ABL gene might happen at or even before the level of hemangioblastic progenitor cells, thus resulting in detection of the BCR/ABL fusion gene in both blood and endothelial cells.

Dendritic Cells Derived In Vitro From Acute Myelogenous Leukemia Cells Stimulate Autologous, Antileukemic T-Cell Responses

Blood ◽  
1999 ◽  
Vol 93 (3) ◽  
pp. 780-786 ◽  
Author(s):  
A. Choudhury ◽  
J.C. Liang ◽  
E.K. Thomas ◽  
L. Flores-Romo ◽  
Q.S. Xie ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Acute Myelogenous Leukemia ◽  
Chromosomal Abnormalities ◽  
Fusion Gene ◽  
Ex Vivo ◽  
Myelogenous Leukemia ◽  
Interleukin 4 ◽  
Acute Myelogenous

Abstract We have previously reported that leukemic dendritic cells (DC) can be generated ex vivo from myelomonocytic precursors in chronic myelogenous leukemia. In this study we report the generation of DC from acute myelogenous leukemia (AML) cells and their potent ability to stimulate leukemia-specific cytolytic activity in autologous lymphocytes. DC were generated in vitro using granulocyte-macrophage colony-stimulating factor +interleukin-4 in combination with either tumor necrosis factor- or CD40 ligand (CD40L). Cells from 19 AML patients with a variety of chromosomal abnormalities were studied for their ability to generate DC. In all but 1 case, cells with the morphology, phenotypic characteristics, and T-cell stimulatory properties of DC could be generated. These cells expressed high levels of major histocompatibility complex class I and class II antigens as well as the costimulatory molecules B7-2 and ICAM-1. In three cases these cells were determined to be of leukemic origin by fluorescence in situ hybridization for chromosomal abnormalities or Western blotting for the inv(16) fusion gene product. Autologous lymphocytes cocultured with AML-derived DC (DC-AL) were able to lyse autologous leukemia targets, whereas little cytotoxicity was noted against autologous, normal cells obtained from the patients during remission. We conclude that leukemia derived DC may be useful for immunotherapy of many AML patients.

Molecular and Phenotypic Analysis of Philadelphia Chromosome-Positive Bilineage Leukemia: Possibility of a Lineage Switch from T-Lymphoid Leukemia Progenitor to Myeloid Cells Via PU.1 Expression.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4362-4362
Author(s):  
Kazuhiro Nishii ◽  
Fumihiko Monma ◽  
Felipe Lorenzo ◽  
Naoyuki Katayama ◽  
Hiroshi Shiku
Keyword(s):  
T Cell ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Leukemic Cells ◽  
Nucleotide Sequencing ◽  
Phenotypic Analysis ◽  
Lymphoid Leukemia ◽  
Lineage Switch ◽  
Philadelphia Chromosome Positive

Abstract The occurrence of acute bilineage leukemia is thought to be the malignant transformation of a myeloid or lymphoid leukemic progenitor with the potential to differentiate into the other lineages; however, the mechanisms of this lineage switch are not well understood. Here, we show the extremely rare case of adult Philadelphia chromosome positive acute bilineage leukemia, characterized by T-cell acute lymphoblastic leukemia, CD7+CD5+CD14−, and acute myelomonocytic leukemia, CD7−CD5−CD14+. Chromosome analysis showed 46,XY,del(7)(p11.2),t(9;22)(q34;q11.2) in all metaphase and leukemic cells expressed a minor BCR/ABL chimeric gene. When the CD5+CD14− and CD5−CD14+ cells were sorted, a fusion gene of BCR/ABL and a same clonal rearranged band of a T-cell receptor (TCR) gene were detected in both populations. Nucleotide sequencing of the TCRg gene revealed the clonal rearrangement of the V8-JGT2 complex in both populations. Over-expression of PU.1, which plays a fundamental role in myelomonocyte development was found in the sorted CD34+CD7+ and CD5−CD14+, but not CD5+CD14− cells. These results suggest that leukemic progenitor cells in the T-lineage with del(7),t(9;22) chromosome have the potential to differentiate into myeloid lineage and enforced PU.1 expression may contribute in part of this phenomenon. Studies of bilineage leukemia will be important for the understanding of lineage commitment and switch in hematopoietic cells.

Dendritic Cells Derived In Vitro From Acute Myelogenous Leukemia Cells Stimulate Autologous, Antileukemic T-Cell Responses

Blood ◽  
1999 ◽  
Vol 93 (3) ◽  
pp. 780-786 ◽  
Author(s):  
A. Choudhury ◽  
J.C. Liang ◽  
E.K. Thomas ◽  
L. Flores-Romo ◽  
Q.S. Xie ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Acute Myelogenous Leukemia ◽  
Chromosomal Abnormalities ◽  
Fusion Gene ◽  
Ex Vivo ◽  
Myelogenous Leukemia ◽  
Interleukin 4 ◽  
Acute Myelogenous

We have previously reported that leukemic dendritic cells (DC) can be generated ex vivo from myelomonocytic precursors in chronic myelogenous leukemia. In this study we report the generation of DC from acute myelogenous leukemia (AML) cells and their potent ability to stimulate leukemia-specific cytolytic activity in autologous lymphocytes. DC were generated in vitro using granulocyte-macrophage colony-stimulating factor +interleukin-4 in combination with either tumor necrosis factor- or CD40 ligand (CD40L). Cells from 19 AML patients with a variety of chromosomal abnormalities were studied for their ability to generate DC. In all but 1 case, cells with the morphology, phenotypic characteristics, and T-cell stimulatory properties of DC could be generated. These cells expressed high levels of major histocompatibility complex class I and class II antigens as well as the costimulatory molecules B7-2 and ICAM-1. In three cases these cells were determined to be of leukemic origin by fluorescence in situ hybridization for chromosomal abnormalities or Western blotting for the inv(16) fusion gene product. Autologous lymphocytes cocultured with AML-derived DC (DC-AL) were able to lyse autologous leukemia targets, whereas little cytotoxicity was noted against autologous, normal cells obtained from the patients during remission. We conclude that leukemia derived DC may be useful for immunotherapy of many AML patients.

scholarly journals Rearrangement of the breakpoint cluster region and expression of P210 BCR-ABL in a "masked" Philadelphia chromosome-positive acute myeloid leukemia

Blood ◽  
1988 ◽  
Vol 72 (5) ◽  
pp. 1829-1832 ◽  
Author(s):  
CM Price ◽  
F Rassool ◽  
MK Shivji ◽  
J Gow ◽  
CJ Tew ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Chimeric Gene ◽  
Leukemic Cells ◽  
Breakpoint Cluster Region ◽  
Cluster Region ◽  
Acute Myeloid

Abstract The Philadelphia (Ph) translocation t(9;22)(q34;q11) occurs frequently in chronic myeloid leukemia (CML) but is less common in acute lymphoblastic leukemia (ALL) and rare in acute myeloid leukemia (AML). In most cases of CML and some cases of Ph+ ALL the protooncogene ABL from 9q34 is translocated to the breakpoint cluster region (bcr) of the BCR gene at 22q11 to form a chimeric gene encoding a novel 210-kd protein (P210 BCR-ABL) with enhanced tyrosine kinase activity. In other patients with Ph+ ALL and Ph+ AML, the breakpoint probably occurs in the first intron of the BCR gene; this results in a smaller chimeric gene which encodes a P190 BCR-ABL. We studied a patient with AML (FAB M6) arising de novo who had a “masked” Ph chromosome in association with extensive karyotypic changes. The leukemic cells initially showed rearrangement of the bcr, presence of a hybrid mRNA, and expression of the P210 BCR-ABL. These changes were absent in remission. These results support the concept that the BCR-ABL chimeric gene plays a crucial role in leukemogenesis but suggest that factors other than the position of the breakpoint in the BCR gene determine the lineage of the target cell for malignant transformation.

DEK/NUP214 Fusion Gene Predicts Good Outcome In Acute Myeloid Leukemia In Complete Remission After Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2386-2386
Author(s):  
Ken Ishiyama ◽  
Akiyoshi Takami ◽  
Shinji Nakao ◽  
Michihiro Hidaka ◽  
Tetsuo Maeda ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Cell Transplantation ◽  
Myeloid Leukemia ◽  
Fusion Gene ◽  
Normal Karyotype ◽  
Chromosome 7 ◽  
Complex Karyotype ◽  
Hematopoietic Stem ◽  
Acute Myeloid

Abstract Abstract 2386 Introduction Acute myeloid leukemia (AML) with chromosomal translocation (6;9)(p23;q34) results in a chimeric fusion gene between DEK/NUP214 (formerly DEK/CAN), and is a rare disease, accounting for approximately 1% of cases. This entity is considered to be a good indication for allogeneic hematopoietic stem cell transplantation (allo-HSCT) due to its poor prognosis and non-responsiveness to chemotherapy. However, whether the prognosis of patients with exclusive DEK/NUP214 abnormality is improved by allo-HSCT has not been demonstrated. We conducted a retrospective study to examine the outcomes of allo-HSCT in AML patients with the DEK/NUP214 gene using the databases of the Japan Society for Hematopoietic Cell Transplantation (JSHCT) and the Japan Cord Blood Bank Network (JCBBN). Methods We identified de novo AML patients who underwent transplant between January 1996 and December 2007 with no prior treatment by allo-HSCT. Clinical features and outcomes of the patients with DEK/NUP214 abnormality and 3 different control groups (patients with chromosome 7 abnormalities, complex karyotype or normal karyotype) were compared. Results Of 4517 AML cases meeting the above criteria, the number of patients with normal karyotype, chromosome 7 abnormalities, complex karyotype and DEK/NUP214 abnormality was 2227, 139, 416 and 64, respectively. The median age of each group was 41, 37, 41 and 34 years, respectively; patients with the DEC/NUP214 abnormality were significantly younger than those with the complex karyotype, and patients with normal chromosomes. Gender was not biased among the groups. Overall survival (OS) of the patients with DEC/NUP214 abnormality at 5 years was 49%, which was superior to the OS of the patients with normal karyotype, chromosome 7 abnormalities and complex karyotype (44%, 30% and 27%, respectively; P < 0.0001; Figure). This trend was significant in HSCT grafts with bone marrow and peripheral blood stem cells. In patients with DEK/NUP214 abnormality, none of the following factors improved survival; combination of gender between patient-donor, dose of total body irradiation prior to HSCT; and use of prophylactic immunosuppressants for graft-versus-host disease. However, the status at HSCT had a significant impact on outcome (5-year OS: 66% in patients in complete remission (CR) at HSCT vs. 31% in non-CR patients; P < 0.001). Analysis exclusively for the patients in CR at HSCT showed similar results as above. Conclusion Our results suggest that patients with the DEK/NUP214 abnormality are more likely to respond to allo-HSCT. Allo-HSCT should be particularly recommended for patients experiencing CR after prior remission-induction chemotherapy. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Impact of chromosomal rearrangement upon DNA methylation patterns in leukemia

Open Medicine ◽  
2017 ◽  
Vol 12 (1) ◽  
pp. 76-85 ◽  
Author(s):  
Hyang-Min Byun ◽  
Shahrooz Eshaghian ◽  
Dan Douer ◽  
Jonathen Trent ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Lymphoblastic Leukemia ◽  
Chromosomal Rearrangements ◽  
Philadelphia Chromosome ◽  
Myelogenous Leukemia ◽  
Tumor Type ◽  
Cell Of Origin ◽  
Hematopoietic Stem ◽  
Gene Translocation ◽  
Chromosomal Lesion

AbstractGenomic instability, including genetic mutations and chromosomal rearrangements, can lead to cancer development. Aberrant DNA methylation occurs commonly in cancer cells. The aim of this study is to determine the effects of a specific chromosomal lesion theBCR-ABLtranslocation t(9:22), in establishing DNA methylation profiles in cancer.Materials and methodsWe compared DNA methylation of 1,505 selected promoter CpGs in chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL) with and without the Philadelphia chromosome t(9:22), CD34+ hematopoietic stem cells transfected withBCR-ABL, and other tumors withoutBCR-ABL(acute promyelocytic leukemia (APL) and gastrointestinal stromal tumors (GIST). In this study, the DNA methylation profile of CML was more closely related to APL, another myeloid leukemia, than Ph+ ALL. Although DNA methylation profiles were consistent within a specific tumor type, overall DNA methylation profiles were no influenced byBCR-ABLgene translocation in the cancers and tissues studied. We conclude that DNA methylation profiles may reflect the cell of origin in cancers rather than the chromosomal lesions involved in leukemogenesis.

Presence of the BCR-ABL mutation Glu255Lys prior to STI571 (imatinib) treatment in patients with Ph+ acute lymphoblastic leukemia

Blood ◽  
2003 ◽  
Vol 102 (2) ◽  
pp. 659-661 ◽  
Author(s):  
Wolf-Karsten Hofmann ◽  
Martina Komor ◽  
Barbara Wassmann ◽  
Letetia C. Jones ◽  
Harald Gschaidmeier ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Kinase Inhibitor ◽  
Mutational Analysis ◽  
Direct Sequencing ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Myelogenous Leukemia ◽  
Leukemic Cells ◽  
Imatinib Treatment

AbstractThe tyrosine kinase inhibitor STI571 (imatinib) binds competitively to the adenosine triphosphate (ATP) binding site of the ABL kinase, thereby inhibiting auto- and substrate phosphorylation of the oncogenic protein BCR-ABL and preventing the activation of downstream signaling pathways. Comparative studies on leukemic cell samples obtained from chronic myelogenous leukemia (CML) and Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) patients before and after treatment with STI571 reported point mutations in resistant samples after a short time of therapy. The aim of this study was to determine whether patients with Ph+ ALL in whom resistance developed as a consequence of the Glu255Lys mutation already harbored this subclone prior to STI571 treatment. First, the migration pattern of cDNAs from 30 bone marrow samples from patients with Ph+ ALL was analyzed by polymerase chain reaction–single strand conformation polymorphism (PCR-SSCP). Thereafter, detailed mutational analysis using genomic DNA was performed on initial STI571-naive bone marrow samples of 4 individuals with Ph+ ALL, for whom the mutation Glu255Lys in association with STI571 treatment had been shown. A 166-bp PCR fragment spanning from nucleotide (nt) 862 to nt 1027 was cloned, and 108 clones per sample were analyzed by direct sequencing. This more sensitive technique revealed the presence of the Glu255Lys mutation in 2 initial samples, one clone each. We identified for the first time the mutation Glu255Lys in STI571-naive leukemic samples of Ph+ ALL patients. The findings suggest that the mutation exists in a very small subpopulation of leukemic cells at the beginning of STI571 therapy.

scholarly journals Tyrosine Kinase Inhibitor Use in Pediatric Philadelphia Chromosome–Positive Acute Lymphoblastic Anemia

Hematology ◽  
2011 ◽  
Vol 2011 (1) ◽  
pp. 361-365 ◽  
Author(s):  
Stephen P. Hunger
Keyword(s):  
Tyrosine Kinase ◽  
Second Generation ◽  
Kinase Inhibitor ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Myelogenous Leukemia ◽  
Kinase Signaling ◽  
New Paradigm ◽  
Hematopoietic Stem ◽  
Philadelphia Chromosome Positive

Abstract Until recently, pediatric Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) was associated with an extremely poor outcome when treated with chemotherapy alone, and only modest survival benefits were obtained with the widespread use of hematopoietic stem cell transplantation (HSCT). The development of first-generation (imatinib) and second-generation (dasatinib and nilotinib) tyrosine kinase inhibitors (TKIs) that target the BCR-ABL1 fusion protein produced by the Ph chromosome revolutionized the treatment of chronic myelogenous leukemia (CML). The Children's Oncology Group (COG) AALL0031 trial showed that the addition of imatinib to intensive chemotherapy did not cause increased toxicity and resulted in 3-year event-free survival rates that were more than double those of historical control data from the pre-imatinib era. These findings create a new paradigm for integrating molecularly targeted agents with conventional chemotherapy and call for a reassessment of the routine use of HSCT for children and adolescents with Ph+ ALL. Second-generation TKIs have theoretical advantages over imatinib, and are now being tested in Ph+ ALL. The focus of contemporary trials is to define the optimal use of chemotherapy, HSCT, and TKI in Ph+ ALL. In the coming years, it is anticipated that additional agents will become available to potentiate TKI therapy and/or circumvent TKI resistance in Ph+ ALL. Recent genomic studies have identified a subtype of high-risk pediatric B-cell-precursor ALL with a gene-expression profile similar to that of Ph+ ALL, suggestive of active kinase signaling. Many of these Ph-like ALL cases harbor chromosome rearrangements and mutations that dysregulate cytokine receptor and kinase signaling, and these leukemias may also be candidates for TKI therapy.

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