Natural killer cell lymphoma shares strikingly similar molecular features with a group of non-hepatosplenic γδ T-cell lymphoma and is highly sensitive to a novel aurora kinase A inhibitor in vitro.
Natural killer (NK) cell lymphomas/leukemias are rare neoplasms with an aggressive clinical behavior. The majority of the cases belong to extranodal NK/T-cell lymphoma, nasal type (ENKTL) in the current WHO classification scheme. Gene-expression profiling (GEP) of 21 ENKTL and NK-cell lymphoma/leukemia patients, 17 NK- and T-cell lines and 5 indolent NK-cell large-granular-lymphocytic proliferation was performed and compared with 125 peripheral T-cell lymphoma (PTCL) patients previously studied. The molecular classifier derived for ENKTL patients was comprised of 84 transcripts with the majority of them contributed by the neoplastic NK cells. The classifier also identified a set of γδ-PTCLs both in the ENKTL cases as well as in cases initially classified as PTCL-not otherwise specified. These γδ-PTCLs expressed transcripts associated with the T-cell receptor (TCR)/CD3 complex, suggesting T cell rather than NK-cell lineage. They were very similar to NK-cell tumors by GEP, but were distinct from cytotoxic (αβ)-PTCL and hepatosplenic T-cell lymphoma, indicating derivation from an ontogenically and functionally distinct subset of γδ T cells. They showed distinct expression of Vγ9, Vδ2 transcripts and were positive for TCRγ, but negative for TCRβ by immunohistochemistry. Targeted inhibition of two oncogenic pathways (AURKA and NOTCH-1) by small-molecular inhibitors induced significant growth arrest in NK-cell lines, thus providing a rationale for clinical trials of these inhibitors in NK-cell malignancies.
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198-3135, USA.
J
J
Iqbal
D D
DD
Weisenburger
A
A
Chowdhury
M Y
MY
Tsai
G
G
Srivastava
T C
TC
Greiner
C
C
Kucuk
K
K
Deffenbacher
J
J
Vose
L
L
Smith
W Y
WY
Au
S
S
Nakamura
M
M
Seto
J
J
Delabie
F
F
Berger
F
F
Loong
Y-H
YH
Ko
I
I
Sng
X
X
Liu
T P
TP
Loughran
J
J
Armitage
W C
WC
Chan
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D064096:Aurora Kinase A; D064127:Aurora Kinases; D006801:Humans; D007694:Killer Cells, Natural / Q000473:pathology*; D008228:Lymphoma, Non-Hodgkin / Q000473:pathology*; D016411:Lymphoma, T-Cell, Peripheral / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D016692:Receptors, Antigen, T-Cell, gamma-delta; D051880:Receptors, Notch / Q000037:antagonists & inhibitors; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D055815:Young Adult
D047428:Protein Kinase Inhibitors; D016692:Receptors, Antigen, T-Cell, gamma-delta; D051880:Receptors, Notch; C576917:AURKA protein, human; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases