Heterogeneity of clonal expansion and maturation-linked mutation acquisition in hematopoietic progenitors in human acute myeloid leukemia.
Recent technological advances led to an appreciation of the genetic complexity of human acute myeloid leukemia (AML), but underlying progenitor cells remain poorly understood because their rarity precludes direct study. We developed a co-culture method integrating hypoxia, aryl hydrocarbon receptor inhibition and micro-environmental support via human endothelial cells to isolate these cells. X-chromosome inactivation studies of the least mature precursors derived following prolonged culture of CD34(+)/CD33(-) cells revealed polyclonal growth in highly curable AMLs, suggesting that mutations necessary for clonal expansion were acquired in more mature progenitors. Consistently, in core-binding factor (CBF) leukemias with known complementing mutations, immature precursors derived following prolonged culture of CD34(+)/CD33(-) cells harbored neither mutation or the CBF mutation alone, whereas more mature precursors often carried both mutations. These results were in contrast to those with leukemias with poor prognosis that showed clonal dominance in the least mature precursors. These data indicate heterogeneity among progenitors in human AML that may have prognostic and therapeutic implications.
1] Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA [2] Division of Hematology, Department of Medicine, University of Washington, Seattle, WA, USA [3] Department of Epidemiology, University of Washington, Seattle, WA, USA.
R B
RB
Walter
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
G S
GS
Laszlo
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
J M
JM
Lionberger
1] Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA [2] Department of Pediatrics, University of Washington, Seattle, WA, USA.
J A
JA
Pollard
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
K H
KH
Harrington
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
C J
CJ
Gudgeon
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
M
M
Othus
Department of Genetic Medicine, Weill Cornell Medical College, New York, NY, USA.
S
S
Rafii
1] Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA [2] Department of Pediatrics, University of Washington, Seattle, WA, USA.
S
S
Meshinchi
1] Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA [2] Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA, USA.
F R
FR
Appelbaum
1] Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA [2] Department of Pediatrics, University of Washington, Seattle, WA, USA.
I D
ID
Bernstein
D018952:Antigens, CD34 / Q000378:metabolism; D015687:Cell Hypoxia; D002469:Cell Separation; D018920:Coculture Techniques; D050660:Core Binding Factors / Q000378:metabolism; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006413:Hematopoietic System; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D011379:Prognosis; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000378:metabolism
D018952:Antigens, CD34; C571163:CD33 protein, human; D050660:Core Binding Factors; D018336:Receptors, Aryl Hydrocarbon; D063268:Sialic Acid Binding Ig-like Lectin 3