scholarly journals Genetically distinct leukemic stem cells in human CD34− acute myeloid leukemia are arrested at a hemopoietic precursor-like stage

2016 ◽  
Vol 213 (8) ◽  
pp. 1513-1535 ◽  
Author(s):  
Lynn Quek ◽  
Georg W. Otto ◽  
Catherine Garnett ◽  
Ludovic Lhermitte ◽  
Dimitris Karamitros ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Genetic Mutation ◽  
Human Cd34 ◽  
Transcription Profiles ◽  
Mature Granulocyte ◽  
Human Acute Myeloid Leukemia ◽  
Stem Cell Populations ◽  
Acute Myeloid

Our understanding of the perturbation of normal cellular differentiation hierarchies to create tumor-propagating stem cell populations is incomplete. In human acute myeloid leukemia (AML), current models suggest transformation creates leukemic stem cell (LSC) populations arrested at a progenitor-like stage expressing cell surface CD34. We show that in ∼25% of AML, with a distinct genetic mutation pattern where >98% of cells are CD34−, there are multiple, nonhierarchically arranged CD34+ and CD34− LSC populations. Within CD34− and CD34+ LSC–containing populations, LSC frequencies are similar; there are shared clonal structures and near-identical transcriptional signatures. CD34− LSCs have disordered global transcription profiles, but these profiles are enriched for transcriptional signatures of normal CD34− mature granulocyte–macrophage precursors, downstream of progenitors. But unlike mature precursors, LSCs express multiple normal stem cell transcriptional regulators previously implicated in LSC function. This suggests a new refined model of the relationship between LSCs and normal hemopoiesis in which the nature of genetic/epigenetic changes determines the disordered transcriptional program, resulting in LSC differentiation arrest at stages that are most like either progenitor or precursor stages of hemopoiesis.

scholarly journals Optimized depletion of chimeric antigen receptor T cells in murine xenograft models of human acute myeloid leukemia

Blood ◽  
2017 ◽  
Vol 129 (17) ◽  
pp. 2395-2407 ◽  
Author(s):  
Sarah K. Tasian ◽  
Saad S. Kenderian ◽  
Feng Shen ◽  
Marco Ruella ◽  
Olga Shestova ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Car T Cells ◽  
Key Points ◽  
Car T ◽  
Human Acute Myeloid Leukemia ◽  
Xenograft Models ◽  
Acute Myeloid

Key Points Depletion of CD123-redirected CAR T cells with monoclonal antibodies preserves leukemia remission in human AML xenograft models. AML CAR T-cell depletion enhances feasibility of subsequent allogeneic stem cell transplantation.

scholarly journals Subpopulation heterogeneity in human acute myeloid leukemia determined by monoclonal antibodies

Blood ◽  
1984 ◽  
Vol 64 (1) ◽  
pp. 275-281 ◽  
Author(s):  
S Pessano ◽  
A Palumbo ◽  
D Ferrero ◽  
GL Pagliardi ◽  
L Bottero ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Monoclonal Antibodies ◽  
Myeloid Leukemia ◽  
Immunofluorescence Assay ◽  
Leukemic Cells ◽  
Mature Granulocyte ◽  
Human Acute Myeloid Leukemia ◽  
Antigenic Phenotype ◽  
The Individual ◽  
Acute Myeloid

Abstract The leukemic population in 63 patients with acute myeloid leukemia (AML) was studied with 15 monoclonal antibodies that detect lineage- related and stage-related antigens on normal hemopoietic cells. Indirect immunofluorescence and fluorescence-activated cell sorting showed that subpopulations of leukemic cells reacted with some or all antibodies, but the percentage of cells reacting with a single antibody varied widely among patients. The composite antigenic phenotype of the various cases, as determined by immunofluorescence assay, did not correlate with the French-American-British morphological classification. Furthermore, some cells in each case failed to express any antigen normally expressed on myelomonocytic precursors from the level of the early CFU-GM to the mature granulocyte or monocyte. In double-fluorescence experiments, the individual cells expressed none, one, or both antigens. These results demonstrate that there is considerable subpopulation heterogeneity in AML. This heterogeneity may considerably limit or complicate the use of monoclonal antibodies for diagnosis, prognosis, and treatment of acute nonlymphocytic leukemia (ANLL).

scholarly journals Diminished AHR Signaling Drives Human Acute Myeloid Leukemia Stem Cell Maintenance

2019 ◽  
Vol 79 (22) ◽  
pp. 5799-5811 ◽  
Author(s):  
Michelle Ly ◽  
Stefan Rentas ◽  
Ana Vujovic ◽  
Nicholas Wong ◽  
Steven Moreira ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Leukemia Stem Cell ◽  
Stem Cell Maintenance ◽  
Human Acute Myeloid Leukemia ◽  
Cell Maintenance ◽  
Acute Myeloid

MYC-induced human acute myeloid leukemia requires a continuing IL-3/GM-CSF costimulus

Blood ◽  
2020 ◽  
Vol 136 (24) ◽  
pp. 2764-2773
Author(s):  
Elizabeth Bulaeva ◽  
Davide Pellacani ◽  
Naoto Nakamichi ◽  
Colin A. Hammond ◽  
Philip A. Beer ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Critical Role ◽  
Immunodeficient Mice ◽  
Gm Csf ◽  
Human Cd34 ◽  
Human Acute Myeloid Leukemia ◽  
Malignant State ◽  
Macrophage Colony ◽  
Acute Myeloid

Abstract Hematopoietic clones with leukemogenic mutations arise in healthy people as they age, but progression to acute myeloid leukemia (AML) is rare. Recent evidence suggests that the microenvironment may play an important role in modulating human AML population dynamics. To investigate this concept further, we examined the combined and separate effects of an oncogene (c-MYC) and exposure to interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and stem cell factor (SCF) on the experimental genesis of a human AML in xenografted immunodeficient mice. Initial experiments showed that normal human CD34+ blood cells transduced with a lentiviral MYC vector and then transplanted into immunodeficient mice produced a hierarchically organized, rapidly fatal, and serially transplantable blast population, phenotypically and transcriptionally similar to human AML cells, but only in mice producing IL-3, GM-CSF, and SCF transgenically or in regular mice in which the cells were exposed to IL-3 or GM-CSF delivered using a cotransduction strategy. In their absence, the MYC+ human cells produced a normal repertoire of lymphoid and myeloid progeny in transplanted mice for many months, but, on transfer to secondary mice producing the human cytokines, the MYC+ cells rapidly generated AML. Indistinguishable diseases were also obtained efficiently from both primitive (CD34+CD38−) and late granulocyte-macrophage progenitor (GMP) cells. These findings underscore the critical role that these cytokines can play in activating a malignant state in normally differentiating human hematopoietic cells in which MYC expression has been deregulated. They also introduce a robust experimental model of human leukemogenesis to further elucidate key mechanisms involved and test strategies to suppress them.

scholarly journals CD96 is a leukemic stem cell-specific marker in human acute myeloid leukemia

2007 ◽  
Vol 104 (26) ◽  
pp. 11008-11013 ◽  
Author(s):  
N. Hosen ◽  
C. Y. Park ◽  
N. Tatsumi ◽  
Y. Oji ◽  
H. Sugiyama ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Specific Marker ◽  
Leukemic Stem Cell ◽  
Human Acute Myeloid Leukemia ◽  
Acute Myeloid
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