The oncogene MYC was one of the first identified BCR-ABL targets required for BCR-ABL leukemogenesis (46,47). Although in some blast crisis CML patients the MYC gene is amplified (2), several BCR-ABL-dependent mechanisms seem to enhance MYC expression at the transcriptional, translational, or post-translational level (39,46,48-51). One of the BCR-ABl pathways regulating MYC expression involves the KH-domain RNA binding protein HNRPK (hnRNP K) (39), a known transcriptional and translational regulator of gene expression (refer ref. 39 and the references therein).
In BCR-ABL-expressing myeloid and lymphoid progenitor cells and in CML-BCCD34+ but not CML-CPCD34+ patient cells, BCR-ABL kinase activity induces HNRPK expression by enhancing Hnrpk gene transcription and mRNA stability through a mechanism that depends on the BCR-ABL-regulated activity of MAPKerk1/2 (39). In fact, BCR-ABL graded expression activates MAPKERK1/2 and increases HNRPK levels in a dose-dependent manner. Knockdown of the RNA binding protein HNRPK inhibits growth factor-independent proliferation, colony formation, and tumorigenesis of BCR-ABL-expressing myeloid progenitors (39). Interestingly, HNRPK downregulation reduces levels of Myc (39), which is transcriptionally and translationally induced by HNRPK (52,53). In BCR-ABL-transformed cells, HNRPK translation-regulatory activity, which depends on phosphorylation of HNRPK on serines 284 and 353 by the BCR-ABL-activated MAPKERK1/2, is necessary for cytokine-independent proliferation, colony formation, and in vivo BCR-ABL leukemogenic potential of the 32D-BCR-ABL cell line and/or of primary CD34+ CML-BC (39). The requirement of HNRPK for BCR-ABL leukemogenesis depends in part on its ability to bind the IRES element of MYC mRNA and enhance MYC mRNA translation (39). In fact, restoration of MYC expression is sufficient to rescue factor-independent colony formation and leukemogenic potential of 32D-BCR-ABL and primary CD34+ CML-BC cells from the inhibitory effects of dominant-negative S284/353A HNRPK (39). Consistent with the existence of a BCR-ABL-MAPK-HNRPK network positively regulating MYC mRNA translation in the advanced phase of CML, MYC protein but not mRNA expression is higher in the CD34+ fraction of CML-BC and -AP marrow cells than in the CD34+ fraction of normal and CML-CP patient marrow cells (39). Thus, one of the molecular mechanisms whereby BCR-ABL enhances MYC expression involves the MAPK-dependent regulation of HNRPK translation regulatory activity. However, increased MYC mRNA levels can be still found in CML-BC patients with amplification of the MYC gene (54,55), and transcriptional, translational, and post-translational mechanisms like those involving the activity of Jak2 kinase (48) may all participate in the regulation of MYC expression in primary CML blast crisis cells.
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