Dynamic single-cell network profiles in acute myelogenous leukemia are associated with patient response to standard induction therapy.
OBJECTIVE
Complete response to induction chemotherapy is observed in approximately 60% of patients with newly diagnosed non-M3 acute myelogenous leukemia (AML). However, no methods exist to predict with high accuracy at the individual patient level the response to standard AML induction therapy.


METHODS
We applied single-cell network profiling (SCNP) using flow cytometry, a tool that allows a comprehensive functional assessment of intracellular signaling pathways in heterogeneous tissues, to two training cohorts of AML samples (n = 34 and 88) to predict the likelihood of response to induction chemotherapy.


RESULTS
In the first study, univariate analysis identified multiple signaling "nodes" (readouts of modulated intracellular signaling proteins) that correlated with response (i.e., AUC(ROC) > or = 0.66; P < or = 0.05) at a level greater than age. After accounting for age, similar findings were observed in the second study. For patients <60 years old, complete response was associated with the presence of intact apoptotic pathways. In patients > or =60 years old, nonresponse was associated with FLT3 ligand-mediated increase in phosphorylated Akt and phosphorylated extracellular signal-regulated kinase. Results were independent of cytogenetics, FLT3 mutational status, and diagnosis of secondary AML.


CONCLUSIONS
These data emphasize the value of performing quantitative SCNP under modulated conditions as a basis for the development of tests highly predictive for response to induction chemotherapy. SCNP provides information distinct from other known prognostic factors such as age, secondary AML, cytogenetics, and molecular alterations and is potentially combinable with the latter to improve clinical decision making. Independent validation studies are warranted.
Kornblau
Steven M
SM
Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Minden
Mark D
MD
Rosen
David B
DB
Putta
Santosh
S
Cohen
Aileen
A
Covey
Todd
T
Spellmeyer
David C
DC
Fantl
Wendy J
WJ
Gayko
Urte
U
Cesano
Alessandra
A
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015331:Cohort Studies; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011237:Predictive Value of Tests; D011446:Prospective Studies; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects; D059010:Single-Cell Analysis; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3 / Q000378:metabolism
C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3