Evaluation of gene expression signatures predictive of cytogenetic and molecular subtypes of pediatric acute myeloid leukemia.
BACKGROUND
Pediatric acute myeloid leukemia is a heterogeneous disease characterized by non-random genetic aberrations related to outcome. The genetic subtype is currently detected by different diagnostic procedures which differ in success rate and/or specificity.


METHODS
We examined the potential of gene expression profiles to classify pediatric acute myeloid leukemia. Gene expression microarray data of 237 children with acute myeloid leukemia were collected and a double-loop cross validation approach was used to generate a subtype-predictive gene expression profile in the discovery cohort (n=157) which was then tested for its true predictive value in the independent validation cohort (n=80). The classifier consisted of 75 probe sets, representing the top 15 discriminating probe sets for MLL-rearranged, t(8;21)(q22;q22), inv(16)(p13q22), t(15;17)(q21;q22) and t(7;12)(q36;p13)-positive acute myeloid leukemia.


RESULTS
These cytogenetic subtypes represent approximately 40% of cases of pediatric acute myeloid leukemia and were predicted with 92% and 99% accuracy in the discovery and independent validation cohort, respectively. However, for NPM1, CEBPA, MLL(-PTD), FLT3(-ITD), KIT, PTPN11 and N/K-RAS gene expression signatures had limited predictive value. This may be caused by a limited frequency of these mutations and by underlying cytogenetics. This latter is exemplified by the fact that different gene expression signatures were discovered for FLT3-ITD in patients with normal cytogenetics and in those with t(15;17)(q21;q22)-positive acute myeloid leukemia, which pointed to HOXB-upregulation being specific for FLT3-ITD(+) cytogenetically normal acute myeloid leukemia.


CONCLUSIONS
In conclusion, gene expression profiling correctly predicted the most prevalent cytogenetic subtypes of pediatric acute myeloid leukemia with high accuracy. In clinical practice, this gene expression signature may replace multiple diagnostic tests for approximately 40% of pediatric acute myeloid leukemia cases whereas only for the remaining cases (predicted as 'acute myeloid leukemia-other') are additional tests indicated. Moreover, the discriminative genes reveal new insights into the biology of acute myeloid leukemia subtypes that warrants follow-up as potential targets for new therapies.
Balgobind
Brian V
BV
Erasmus MC-Sophia Children's Hospital, Department of Pediatric Oncology and Hematology, Room Sp2456, PO Box 2060, 3000 CB Rotterdam, Netherlands.
Van den Heuvel-Eibrink
Marry M
MM
De Menezes
Renee X
RX
Reinhardt
Dirk
D
Hollink
Iris H I M
IH
Arentsen-Peters
Susan T J C M
ST
van Wering
Elisabeth R
ER
Kaspers
Gertjan J L
GJ
Cloos
Jacqueline
J
de Bont
Evelien S J M
ES
Cayuela
Jean-Michel
JM
Baruchel
Andre
A
Meyer
Claus
C
Marschalek
Rolf
R
Trka
Jan
J
Stary
Jan
J
Beverloo
H Berna
HB
Pieters
Rob
R
Zwaan
C Michel
CM
den Boer
Monique L
ML
D000328:Adult; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D002648:Child; D020732:Cytogenetic Analysis; D020869:Gene Expression Profiling; D015321:Gene Rearrangement; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D051788:Myeloid-Lymphoid Leukemia Protein; D000090243:Nucleophosmin; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D014408:Biomarkers, Tumor; C497422:KMT2A protein, human; C000716967:NPM1 protein, human; D012333:RNA, Messenger; D000090243:Nucleophosmin; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase