Impaired Differentiation in Blast Crisis Chronic Myeloid Leukemia Loss of CEBP and CEBPb Expression

The inability of blast crisis CML-BC myeloid progenitors to undergo terminal differentiation primarily depends on marked downregulation of C/EBPa (20), a basic region leucine zipper transcription regulator essential for granulocytic differentiation (refer Ref. 20 and the references therein). The importance of loss of C/EBPa activity as a central mechanism leading to differentiation arrest of CML myeloid blasts is supported by three lines of evidence: (i) ectopic C/EBPa expression induces maturation of differentiation-arrested BCR-ABL-expressing myeloid

BCRMBL-dependent mechanisms of CML. disease progression 11 í p210 BCft/ABL _-

hnRNP E2

Differentiation airest

La MriPK PI-3K/Akr STAT5 Jak2

I MYC mTOR BAD Bel-XL

Enhanced SURVIVAL MITOGENIC Signals p-catenm self renewal

DNA-PK ATft ROS

• increased genetic/ chrorro&omal instability

- Bcr/abl mutations p53 mutations [30XM-BQ p!6 mutations {50% L-&C) pl4MRF mut. (SO«. L-BC) Rb mur.Akf.(]8%L-8C)

Activating signal Inhibitory signal Tumor suppressor

FIGURE 2 BCR-ABL-dependent mechanisms of chronic myeloid leukemia (CML)-disease progression. Effects of increased BCR-ABL expression and activity on downstream targets modulating differentiation, proliferation, survival, and genomic stability of CML progenitors. Abbreviations: ATR, ataxia teleoegectasia related; ROS, reactive oxygen species.

precursors (20); (ii) a blast crisis-like process emerges in mice transplanted with BCR-ABL-transduced Cebpa-null, but not heterozygous or wild type fetal liver cells (42); and (iii) genetic or functional inactivation of C/EBPa is a common event in differentiation-arrested acute myeloid leukemia blasts (reviewed in Ref. 43). In BCR-ABL-expressing myeloid progenitor cells, loss of C/EBPa depends on the BCR-ABL-induced activity of the RNA binding protein hnRNP E2 that, upon interaction with the 50 untranslated region of CEBPA mRNA, inhibits CEBPA translation (20). In fact, the C/EBPa protein but not mRNA expression is downmodulated in primary bone marrow cells from CML-BC patients and inversely correlates with BCR-ABL levels (20), suggesting that the effects are dose-dependent. Accordingly, the hnRNP E2 expression is inversely correlated with that of C/EBPa (23), as hnRNP E2 levels were abundant in CML-blast crisis but undetectable in CML-chronic phase mononuclear marrow cells.

Like C/EBPa, C/EBPb is a transcription regulator that controls myeloid maturation and a functional equivalent of C/EBPa based on its ability to restore granulocytic differentiation in C/EBPa null mice (44). In BCR-ABL-expressing cells, imatinib treatment shifts c/ebpb mRNA onto polysomes. The effect of imatinib is mediated by the activity of the RNA binding protein CUGBP1 that binds a CUG-repeat region located between the first and the third AUG of c/ebpb mRNA (45). Like C/EBPa, expression of C/EBPb is repressed in primary CML blast crisis progenitors (45), suggesting that loss of C/EBPa and C/EBPb activity contributes to differentiation arrest and aggressive behavior of CML blast crisis cells. Accordingly, levels of CUGBP1 were higher in normal and CML chronic phase CD34+ cells than in CML blast crisis CD34+ progenitors (45). Ectopic expression or inducible activation of C/EBPb inhibits proliferation and promotes granulocytic maturation of differentiation-arrested murine BCR-ABL + cells through a mechanism that depends on C/EBPb transcriptional activity (45). Thus, the antileukemic effects of C/EBPb suggest that enhanced C/EBPb expression might contribute to the cytotoxic effects of imatinib. Because transition to blast crisis is associated with accumulation of genetic abnormalities (i.e., loss of p53 function) and changes in gene expression (i.e., down-modulation of c/eBPw and C/EBPb) (20,45), c-Hyc, the cellular homologue of the myelocytomatosis virus a complete loss of C/EBPs activity might be necessary to disrupt the differentiation potential of CML blast crisis progenitors.

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