Gene-expression profiling identifies distinct subclasses of core binding factor acute myeloid leukemia.
Core binding factor (CBF) leukemias, characterized by either inv(16)/t(16;16) or t(8;21), constitute acute myeloid leukemia (AML) subgroups with favorable prognosis. However, there exists substantial biologic and clinical heterogeneity within these cytogenetic groups that is not fully reflected by the current classification system. To improve the molecular characterization we profiled gene expression in a large series (n = 93) of AML patients with CBF leukemia [(inv (16), n = 55; t(8;21), n = 38)]. By unsupervised hierarchical clustering we were able to define a subgroup of CBF cases (n = 35) characterized by shorter overall survival times (P = .03). While there was no obvious correlation with fusion gene transcript levels, FLT3 tyrosine kinase domain, KIT, and NRAS mutations, the newly defined inv(16)/t(8;21) subgroup was associated with elevated white blood cell counts and FLT3 internal tandem duplications (P = .011 and P = .026, respectively). Supervised analyses of gene expression suggested alternative cooperating pathways leading to transformation. In the "favorable" CBF leukemias, antiapoptotic mechanisms and deregulated mTOR signaling and, in the newly defined "unfavorable" subgroup, aberrant MAPK signaling and chemotherapy-resistance mechanisms might play a role. While the leukemogenic relevance of these signatures remains to be validated, their existence nevertheless supports a prognostically relevant biologic basis for the heterogeneity observed in CBF leukemia.
Bullinger
Lars
L
Department of Internal Medicine III, University of Ulm, Ulm, Germany. lars.bullinger@uniklinik-ulm.de
Rücker
Frank G
FG
Kurz
Stephan
S
Du
Juan
J
Scholl
Claudia
C
Sander
Sandrine
S
Corbacioglu
Andrea
A
Lottaz
Claudio
C
Krauter
Jürgen
J
Fröhling
Stefan
S
Ganser
Arnold
A
Schlenk
Richard F
RF
Döhner
Konstanze
K
Pollack
Jonathan R
JR
Döhner
Hartmut
H
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D002869:Chromosome Aberrations; D007446:Chromosome Inversion; D016000:Cluster Analysis; D050660:Core Binding Factors / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000145:classification / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D015996:Survival Rate; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
D014408:Biomarkers, Tumor; D050660:Core Binding Factors; C497970:FLT3 protein, human; D019009:Proto-Oncogene Proteins c-kit; D051941:fms-Like Tyrosine Kinase 3