Deregulation and cross talk among sonic hedgehog, wnt, hox and notch signaling in chronic myeloid leukemia progression

ABSTRACT Deciphering the BCR-ABL-independent signaling exploited in chronic myeloid leukemia (CML) progression is an important aspect in cancer stem-cell biology. CML stem-cell compartment

is dynamic as it progresses to terminal blast crisis where myeloid and lymphoid blasts fail to differentiate. We demonstrate cross-regulation of signaling network involving Sonic hedgehog

(Shh), Wnt, Notch and Hox for the inexorable blastic transformation of CD34+ CML cells. Significant upregulation in Patched1, Frizzled2, Lef1, CyclinD1, p21 (_P_⩽0.0002) and downregulation

of HoxA10 and HoxB4 (_P_⩽0.0001) transcripts in CD34+ cells distinguish blast crisis from chronic CML. We report Shh-dependent Stat3 activation orchestrates these mutually interconnected

signaling pathways. Stimulation of CD34+ CML cells with either soluble Shh or Wnt3a did not activate Akt or p44/42–mitogen activated protein kinase (MAPK) pathways. Interestingly, unlike

dominant negative Stat3_β_, introduction of constitutive active Stat3 in CD34+ CML cells induces cross-regulation in gene expression. Additionally, Shh and Wnt3a-dependent regulation of

cyclin-dependent kinase inhibitors (CDKI) in CML suggests their role in the network. Taken together, our findings propose that deregulation in the form of hyperactive Shh and Wnt with

repressed Notch and Hox pathways involving Stat3, Gli3, _β_-catenin, CyclinD1, Hes1, HoxA10 and p21 might act synergistically to form an important hub in CML progression. Access through your

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Scholar  Download references ACKNOWLEDGEMENTS We thank Drs David Scadden, Jon Aster, Tom Kadesch, Hans Clevers, Chris Albanese, Toshiyuki Sakai, Jacqueline Bromberg and John Clifford for

various molecular constructs. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Structural Genomics Section and Biophysics Division, Saha Institute of Nuclear Physics, Kolkata, West Bengal,

India A Sengupta & S Banerjee * Clinical Haematology Service, Park Clinic, Kolkata, West Bengal, India D Banerjee & S Chandra * Department of Hematooncology, National Medical College

& Hospital, Kolkata, West Bengal, India S K Banerji * Department of Hematooncology, Cancer Centre Welfare Home & Research Institute, Kolkata, West Bengal, India R Ghosh & R Roy

Authors * A Sengupta View author publications You can also search for this author inPubMed Google Scholar * D Banerjee View author publications You can also search for this author inPubMed 

Google Scholar * S Chandra View author publications You can also search for this author inPubMed Google Scholar * S K Banerji View author publications You can also search for this author

inPubMed Google Scholar * R Ghosh View author publications You can also search for this author inPubMed Google Scholar * R Roy View author publications You can also search for this author

inPubMed Google Scholar * S Banerjee View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to S Banerjee. ADDITIONAL

INFORMATION Supplementary Information accompanies the paper on the Leukemia Web site (http://www.nature.com/leu) SUPPLEMENTARY INFORMATION SUPPLEMENTARY TABLE 1 (DOC 83 KB) SUPPLEMENTARY

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Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Sengupta, A., Banerjee, D., Chandra, S. _et al._ Deregulation and cross talk among Sonic hedgehog, Wnt, Hox and Notch signaling

in chronic myeloid leukemia progression. _Leukemia_ 21, 949–955 (2007). https://doi.org/10.1038/sj.leu.2404657 Download citation * Received: 28 November 2006 * Revised: 06 February 2007 *

Accepted: 13 February 2007 * Published: 15 March 2007 * Issue Date: May 2007 * DOI: https://doi.org/10.1038/sj.leu.2404657 SHARE THIS ARTICLE Anyone you share the following link with will be

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initiative KEYWORDS * Shh * Wnt * Notch * Hox * CML