Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gene targeting and overexpression studies have demonstrated the importance of the clustered homeobox (HOX) genes in hematopoesis. In addition, global HOX gene dysregulation is found in the majority of cases of acute myeloid leukemia (AML) and many cases of acute lymphoblastic leukemia (ALL), and substantial evidence exists to suggest that aberrant expression of HOX genes contributes to the pathogenesis of leukemia. However, although individual HOX genes are rearranged in rare cases of AML and HOX genes are known transcriptional targets of certain leukemia-associated fusion proteins, such as those involving the mixed lineage leukemia (MLL) gene, in the majority of cases, the upstream regulators of HOX genes are unknown. The CDX family of non-clustered homeobox genes are known developmental regulators of HOX gene expression. We have recently demonstrated that Cdx4 is expressed in adult murine bone marrow where its expression pattern follows that of Hox genes. We also demonstrated that CDX2 is expressed in the majority, and that CDX4 is expressed in almost a quarter, of AML patient samples. For CDX2, this expression was predominantly monoallelic but was not associated with coding sequence or promoter mutations, gene amplification, or aberrant promoter methylation. In addition, stable knockdown of CDX2 resulted in a loss of proliferation and clonogenicity in AML cell lines, and bone marrow retrovirally engineered to express either Cdx2 or Cdx4 generated AML in transplant recipients. Cdx4 was shown to cooperate with the known Hox cofactor Meis1a, and structure-function experiments confirmed that the transcription factor function of Cdx4 was required for transformation. Finally, expression of either Cdx2 or Cdx4 generated a dysregulated Hox gene program in normal hematopoietic progenitors and in leukemic tissue. Taken together, these studies implicate CDX proteins as master regulators of HOX gene regulation in AML.
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PMID:HOX gene regulation in acute myeloid leukemia: CDX marks the spot? 1788 1

During the past decade it was recognized that homeobox gene families such as the clustered Hox genes play pivotal roles both in normal and malignant hematopoiesis. More recently, similar roles have also become apparent for members of the ParaHox gene cluster, evolutionarily closely related to the Hox gene cluster. This is in particular found for the caudal-type homeobox genes (Cdx) genes, known to act as upstream regulators of Hox genes. The CDX gene family member CDX2 belongs to the most frequent aberrantly expressed proto-oncogenes in human acute leukemias and is highly leukemogenic in experimental models. Correlative studies indicate that CDX2 functions as master regulator of perturbed HOX gene expression in human acute myeloid leukemia, locating this ParaHox gene at a central position for initiating and maintaining HOX gene dysregulation as a driving leukemogenic force. There are still few data about potential upstream regulators initiating aberrant CDX2 expression in human leukemias or about critical downstream targets of CDX2 in leukemic cells. Characterizing this network will hopefully open the way to therapeutic approaches that target deregulated ParaHox genes in human leukemia.
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PMID:Beyond Hox: the role of ParaHox genes in normal and malignant hematopoiesis. 2254 80

Cdx and Hox proteins are homeodomain transcription factors that regulate hematopoiesis. Transcription of the HOX and CDX genes decreases during normal myelopoiesis, but is aberrantly sustained in leukemias with translocation or partial tandem duplication of the MLL1 gene. Cdx4 activates transcription of the HOXA9 and HOXA10 genes, and HoxA10 activates CDX4 transcription. The events that break this feedback loop, permitting a decreased Cdx4 expression during normal myelopoiesis, were previously undefined. In the current study, we find that HoxA9 represses CDX4 transcription in differentiating myeloid cells, antagonizing activation by HoxA10. We determine that tyrosine phosphorylation of HoxA10 impairs transcriptional activation of CDX4, but tyrosine phosphorylation of HoxA9 facilitates repression of this gene. As HoxA9 and HoxA10 are phosphorylated during myelopoiesis, this provides a mechanism for differentiation stage-specific Cdx4 expression. HoxA9 and HoxA10 are increased in cells expressing Mll-Ell, a leukemia-associated MLL1 fusion protein. We find that Mll-Ell induces a HoxA10-dependent increase in Cdx4 expression in myeloid progenitor cells. However, Cdx4 decreases in a HoxA9-dependent manner on exposure of Mll-Ell-expressing cells to differentiating cytokines. Leukemia-associated, constitutively active mutants of Shp2 block cytokine-induced tyrosine phosphorylation of HoxA9 and HoxA10. In comparison with myeloid progenitor cells that are expressing Mll-Ell alone, we find increased CDX4 transcription and Cdx4 expression in cells co-expressing Mll-Ell plus constitutively active Shp2. Increased Cdx4 expression is sustained on exposure of these cells to differentiating cytokines. Our results identify a mechanism for increased and sustained CDX4 transcription in leukemias co-overexpressing HoxA9 and HoxA10 in combination with constitutive activation of Shp2. This is clinically relevant, because MLL1 translocations and constitutive Shp2 activation co-exist in human myeloid leukemias.
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PMID:Regulation of CDX4 gene transcription by HoxA9, HoxA10, the Mll-Ell oncogene and Shp2 during leukemogenesis. 2553 30