Gene expression changes associated with progression and response in chronic myeloid leukemia

Abstract

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.

Fig. 1.

Genes associated with CML progression. Samples from patients with of CML cases in chronic phase, accelerated by cytogenetic criteria only, accelerated phase, blast crisis, and blast crisis “in remission” were compared to a pool of chronic phase RNA (See Materials and Methods for details). Approximately 3,500 genes were significantly associated with progressive disease at a significance level of P < 10⁻¹¹. Each row represents one sample, and each column represents one gene. Red color indicates overexpression relative to the control pool, and green color indicates low expression.

Fig. 2.

Comparison of CML blasts to normal CD34⁺ cells and correction for the pattern of gene expression. (A) Phase genes were corrected for normal CD34⁺ gene expression (ANOVA, P < 1 × 10⁻⁸). The gene expression of normal CD34⁺ cells was subtracted from each disease sample. The resulting pattern reflects genes associated with progression independent of normal blast biology. (B) Relative gene expression of the “top ten” genes found to be up-regulated in advanced phase disease compared to chronic phase.

Fig. 3.

Gene expression in patients with resistance to Imatinib failure cases. Cases were ranked and sorted by the correlation of summed gene expression, with cases representing the most “chronic phase-like” and most “blast crisis-like” forming the boundaries of gene expression patterns. Cases that had a poor response to imatinib are designated by a blue dot in the “IM-cases” box to the right of the heat map. The red arrows point to the two cases that had the T315I Abl mutation.