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 Stat3β, 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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Jamieson CHM, Ailles LE, Dylla SJ, Muijtjens M, Jones C, Zehnder JL et al. Granulocyte-Macrophage progenitors as candidate leukemic stem cells in blast crisis CML. N Engl J Med 2004; 351: 657–667.
Castor A, Nilsson L, Grundstrom IA, Buitenhuis M, Ramirez C, Anderson K et al. Distinct patterns of hematopoietic stem cell involvement in acute lymphoblastic leukemia. Nat Med 2005; 11: 630–637.
Krivtsov AV, Twomey D, Feng Z, Stubbs MC, Wang Y, Faber J et al. Transformation from committed progenitor to leukemia stem cell initiated by MLL-AF9. Nature 2006; 442: 818–822.
Bhatia R, Holtz M, Niu N, Gray R, Snyder DS, Sawyers CL et al. Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenic remission following imatinib mesylate treatment. Blood 2003; 101: 4701–4707.
Huntly BJP, Gilliland DG . Leukemia stem cells and the evolution of cancer-stem-cell research. Nat Rev Cancer 2005; 5: 311–321.
Duncan AW, Rattis FM, Dimascio LN, Congdon KL, Pazianos G, Zhao C et al. Integration of Notch and Wnt signaling in hematopoietic stem cell maintenance. Nat Immunol 2005; 6: 314–322.
Cheng T, Rodrigues N, Shen H, Yang YG, Dombkowski D, Sykes M et al. Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science 2000; 287: 1804–1808.
Cheng T, Rodrigues N, Dombkwoski D, Stier S, Scadden DT . Stem cell repopulation efficiency but not pool size is governed by p27kip1. Nat Med 2000; 6: 1235–1240.
Taipale J, Beachy PA . The hedgehog and Wnt signaling pathways in cancer. Nature 2001; 411: 349–354.
Bhardwaj G, Murdoch B, Wu D, Baker DP, Williams KP, Chadwick K et al. Sonic hedgehog induces the proliferation of primitive human hematopoietic cells via BMP regulation. Nat Immunol 2001; 2: 172–180.
Grabher C, Boehmer H, Look AT . Notch1 activation in the molecular pathogenesis of T-cell acute lymphoblastic leukemia. Nat Rev Cancer 2006; 6: 347–359.
Kamakura S, Oishi K, Yoshimatsu T, Nakafuku M, Masuyama N, Gotoh Y . Notch1 activation in the molecular pathogenesis of T-cell acute lymphoblastic leukemia. Nat Cell Biol 2004; 6: 547–554.
Murata K, Hattori M, Hirai N, Shinozuka Y, Hirata H, Kageyama R et al. Hes1 directly controls cell proliferation through the transcriptional repression of p27kip1. Mol Cell Biol 2005; 25: 4262–4271.
Sarmento LM, Huang H, Limon A, Gordon W, Fernandes J, Tavares MJ et al. Notch1 modulates timing of G1-S progression by inducing SKP2 transcription and p27kip1 degradation. J Exp Med 2006; 202: 157–168.
Ysebaert L, Chicanne G, Demur C, Toni FD, Houdellier NP, Ruidavets JB et al. Expression of β-catenin by acute myeloid leukemia cells predicts enhanced clonogenic capacities and poor prognosis. Leukemia 2006; 20: 1211–1216.
Lu D, Zhao Y, Tawatao R, Cottam HB, Sen M, Leoni LM et al. Activation of the Wnt signaling pathway in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 2004; 101: 3118–3123.
Zweidler-McKay PA, He Y, Xu L, Rodriguez CG, Karnell FG, Carpenter AC et al. Notch signaling is a potent inducer of growth arrest and apoptosis in a wide range of B-cell malignancies. Blood 2005; 106: 3898–3906.
Sanchez P, Hemandez AM, Stecca B, Kahler AJ, Degueme AM, Barrett A et al. Inhibition of prostate cancer proliferation by interference with sonic hedgehog-Gli1 signaling. Proc Natl Acad Sci USA 2004; 101: 12561–12566.
Sengupta A, Banerjee D, Chandra S, Banerjee S . Gene therapy for BCR-ABL+ human CML with dual phosphorylation resistant p27kip1 and stable RNA interference using an EBV vector. J Gene Med 2006; 8: 1251–1261.
Zhu J, Zhang Y, Joe GJ, Pompetti R, Emerson SG . NF-Ya activates multiple hematopoietic stem cell (HSC) regulatory genes and promotes HSC self-renewal. Proc Natl Acad Sci USA 2005; 102: 11728–11733.
Magnusson M, Brun AC, Miyake N, Larsson J, Ehinger M, Bjornsson JM et al. HoxA10 is a critical regulator for hematopoietic stem cells and erythroid/megakaryocyte development. Blood 2007; (e-pub: Jan. 18, PMID: 17234739).
Bjornsson JM, Andersson E, Lundstrom P, Larsson N, Xu X, Repetowska E et al. Proliferation of primitive myeloid progenitors can be reversibly induced by HoxA10. Blood 2001; 98: 3301–3308.
Antonchuk J, Sauvageau G, Humphries RK . HoxB4-induced expansion of adult hematopoietic stem cells ex vivo. Cell 2002; 109: 39–45.
Beslu N, Krosl J, Laurin M, Mayotte N, Humphries KR, Sauvageau G . Molecular interactions involved in HoxB4-induced activation of HSC self-renewal. Blood 2004; 104: 2307–2314.
Riobo NA, Lu K, Ai X, Haines GM, Emerson CP . Phosphoinositide 3-kinase and Akt are essential for sonic hedgehog signaling. Proc Natl Acad Sci USA 2006; 103: 4505–4510.
Coppo P, Dusanter-Fourt I, Millot G, Nogueira MM, Dugray A, Bonnet ML et al. Constitutive and specific activation of Stat3 by BCR-ABL in embryonic stem cells. Oncogene 2003; 22: 4102–4110.
Leslie K, Lang C, Devgan G, Azare J, Berishaj M, Gerald W et al. CyclinD1 is transcriptionally regulated by and required for transformation by activated signal transducer and activator of transcription 3. Cancer Res 2006; 66: 2544–2552.
Kawada M, Seno H, Uenoyama Y, Sawabu T, Kanda N, Fukui H et al. Signal transducers and activators of transcription 3 activation is involved in nuclear accumulation of β-catenin in colorectal cancer. Cancer Res 2006; 66: 2913–2917.
Walkley CR, Fero ML, Chien WM, Purton LE, McArthur GA . Negative cell-cycle regulators cooperatively control self-renewal and differentiation of hematopoietic stem cells. Nat Cell Biol 2005; 7: 172–178.
Weng AP, Millholland JM, Yashiro-Ohtani Y, Arcangeli ML, Lau A, Wai C et al. c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. Genes Dev 2006; 20: 2096–2109.
Androutsellis-Theotokis A, Leker RR, Soldner F, Hoeppner DJ, Ravin R, Poser SW et al. Notch signaling regulates stem cell numbers in vitro and in vivo. Nature 2006; 442: 823–826.
Steidl U, Kronenwett R, Rohr U, Fenk R, Kliszewski S, Maercker C et al. Gene expression profiling identifies significant differences between the molecular phenotypes of bone marrow-derived and circulating human CD34+ hematopoietic stem cells. Blood 2002; 99: 2037–2044.
Kramer A, Loffler H, Bergmann J, Hochhaus A, Hehlmann R . Proliferating status of peripheral blood progenitor cells from patients with BCR/ABL-positive chronic myelogenous leukemia. Leukemia 2001; 15: 62–68.
Radich JP, Dai H, Mao M, Oehler V, Schelter J, Druker B et al. Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc Natl Acad Sci USA 2006; 103: 2794–2799.
Zheng C, Li L, Haak M, Brors B, Frank O, Giehl M et al. Gene expression profiling of CD34+ cells identifies a molecular signature of chronic myeloid leukemia blast crisis. Leukemia 2006; 20: 1028–1034.
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
Corresponding author
Additional information
Supplementary Information accompanies the paper on the Leukemia Web site (http://www.nature.com/leu)
Rights 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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.leu.2404657
Keywords
This article is cited by
-
Thymoquinone-chemotherapeutic combinations: new regimen to combat cancer and cancer stem cells
Naunyn-Schmiedeberg's Archives of Pharmacology (2020)
-
Chronic myeloid leukaemia cells require the bone morphogenic protein pathway for cell cycle progression and self-renewal
Cell Death & Disease (2018)
-
Expression differences of genes in the PI3K/AKT, WNT/b-catenin, SHH, NOTCH and MAPK signaling pathways in CD34+ hematopoietic cells obtained from chronic phase patients with chronic myeloid leukemia and from healthy controls
Clinical and Translational Oncology (2018)
-
Aberrant activation of CaMKIIγ accelerates chronic myeloid leukemia blast crisis
Leukemia (2016)
-
Deregulated hedgehog pathway signaling is inhibited by the smoothened antagonist LDE225 (Sonidegib) in chronic phase chronic myeloid leukaemia
Scientific Reports (2016)