Gene expression changes associated with progression and response in chronic myeloid leukemia.
Chronic myeloid leukemia (CML) is a hematopoietic stem cell disease with distinct biological and clinical features. The biologic basis of the stereotypical progression from chronic phase through accelerated phase to blast crisis is poorly understood. We used DNA microarrays to compare gene expression in 91 cases of CML in chronic (42 cases), accelerated (17 cases), and blast phases (32 cases). Three thousand genes were found to be significantly (P < 10(-10)) associated with phase of disease. A comparison of the gene signatures of chronic, accelerated, and blast phases suggest that the progression of chronic phase CML to advanced phase (accelerated and blast crisis) CML is a two-step rather than a three-step process, with new gene expression changes occurring early in accelerated phase before the accumulation of increased numbers of leukemia blast cells. Especially noteworthy and potentially significant in the progression program were the deregulation of the WNT/beta-catenin pathway, the decreased expression of Jun B and Fos, alternative kinase deregulation, such as Arg (Abl2), and an increased expression of PRAME. Studies of CML patients who relapsed after initially successful treatment with imatinib demonstrated a gene expression pattern closely related to advanced phase disease. These studies point to specific gene pathways that might be exploited for both prognostic indicators as well as new targets for therapy.
Radich
Jerald P
JP
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. jradich@fhcrc.org
Dai
Hongyue
H
Mao
Mao
M
Oehler
Vivian
V
Schelter
Jan
J
Druker
Brian
B
Sawyers
Charles
C
Shah
Neil
N
Stock
Wendy
W
Willman
Cheryl L
CL
Friend
Stephen
S
Linsley
Peter S
PS
D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D004268:DNA-Binding Proteins / Q000378:metabolism; D018450:Disease Progression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D051741:Kruppel-Like Transcription Factors; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics*; D020648:Peptide Elongation Factor 1 / Q000378:metabolism; D010879:Piperazines / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D012008:Recurrence; D014157:Transcription Factors / Q000378:metabolism
D000970:Antineoplastic Agents; D001549:Benzamides; D004268:DNA-Binding Proteins; D051741:Kruppel-Like Transcription Factors; C085969:MZF1 protein, human; D020648:Peptide Elongation Factor 1; D010879:Piperazines; D011743:Pyrimidines; D014157:Transcription Factors; D000068877:Imatinib Mesylate