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Published in: Journal of Experimental & Clinical Cancer Research 1/2011

Open Access 01-12-2011 | Research

Activation of the hedgehog pathway in chronic myelogeneous leukemia patients

Authors: Bing Long, Huanling Zhu, Cuixia Zhu, Ting Liu, Wentong Meng

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2011

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Abstract

Background

Hedgehog (Hh) signaling pathway is involved in regulation of many tissues development and oncogenesis. Recently, Hh signaling has been identified as a required functional pathway for leukemia stem cells(LSCs), and loss of this pathway impairs leukemia progression.

Objectives

The aim of this study was to determine the expression of Hedgehog signaling molecules in Chronic Myelogeneous Leukemia (CML) patients and normal people by semiquantitative polymerase chain reaction (PCR) and to correlate mRNA expression to patients' clinical data.

Results

Here, we showed that Sonic hedgehog (Shh), Smoothened (Smo), and Gli1 genes of Hh signaling were significantly upregulated in CML patients when compared with normal people (P < 0.001). The levels of Shh, Smo mRNA in chronic phase of CML patients were obviously lower than that in blast crisis (p < 0.05). There were no significant differences of Shh, Ptch1, Smo, Gli1 mRNA expression found when comparing CML patients of chronic phase(CP) with imatinib(IM) treated or not(p > 0.05).

Conclusions

These findings suggested that activation of the Hh pathway maybe associated with CML progression. Treatment of CML with imatinib, a selective inhibitor of the BCR-ABL tyrosine kinase inhibitor, has no significant influence on the inhibition of Hh pathway of CML-CP patients.
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Literature
1.
go back to reference Graham SM, Jorgensen HG, Allan E, Pearson C, Alcorn MJ, Richmond L, Holyoake TL: Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood. 2002, 99 (1): 319-325. 10.1182/blood.V99.1.319.CrossRefPubMed Graham SM, Jorgensen HG, Allan E, Pearson C, Alcorn MJ, Richmond L, Holyoake TL: Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood. 2002, 99 (1): 319-325. 10.1182/blood.V99.1.319.CrossRefPubMed
2.
go back to reference Jorgensen HG, Allan EK, Jordanides NE, Mountford JC, Holyoake TL: Nilotinib exerts equipotent antiproliferative effects to imatinib and does not induce apoptosis in CD34+ CML cells. Blood. 2007, 109 (9): 4016-4019. 10.1182/blood-2006-11-057521.CrossRefPubMed Jorgensen HG, Allan EK, Jordanides NE, Mountford JC, Holyoake TL: Nilotinib exerts equipotent antiproliferative effects to imatinib and does not induce apoptosis in CD34+ CML cells. Blood. 2007, 109 (9): 4016-4019. 10.1182/blood-2006-11-057521.CrossRefPubMed
3.
go back to reference Zhao C, Chen A, Jamieson CH, Fereshteh M, Abrahamsson A, Blum J, Kwon HY, Kim J, Chute JP, Rizzieri D, Munchhof M, VanArsdale T, Beachy PA, Reya T: Hedgehog signaling is essential for maintenance of cancer stem cells in myeloid leukemia. Nature. 2009, 458 (7239): 776-779. 10.1038/nature08255.PubMedCentralCrossRefPubMed Zhao C, Chen A, Jamieson CH, Fereshteh M, Abrahamsson A, Blum J, Kwon HY, Kim J, Chute JP, Rizzieri D, Munchhof M, VanArsdale T, Beachy PA, Reya T: Hedgehog signaling is essential for maintenance of cancer stem cells in myeloid leukemia. Nature. 2009, 458 (7239): 776-779. 10.1038/nature08255.PubMedCentralCrossRefPubMed
4.
go back to reference Dierks C, Beigi R, Guo GR, Zirlik K, Stegert MR, Manley P, Trussell C, Schmitt-Graeff A, Landwerlin K, Veelken H, Warmuth M: Expansion of BCR-ABL positive leukemic stem cells is dependent on Hedgehog pathway activation. Cancer cell. 2008, 14 (3): 238-249. 10.1016/j.ccr.2008.08.003.CrossRefPubMed Dierks C, Beigi R, Guo GR, Zirlik K, Stegert MR, Manley P, Trussell C, Schmitt-Graeff A, Landwerlin K, Veelken H, Warmuth M: Expansion of BCR-ABL positive leukemic stem cells is dependent on Hedgehog pathway activation. Cancer cell. 2008, 14 (3): 238-249. 10.1016/j.ccr.2008.08.003.CrossRefPubMed
5.
6.
go back to reference Huangfu D, Anderson KV: Signaling from Smo to Ci/Gli: conservation and divergence of Hedgehog pathways from Drosophila to vertebrates. Development. 2006, 133 (1): 3-14. 10.1242/dev.02169.CrossRefPubMed Huangfu D, Anderson KV: Signaling from Smo to Ci/Gli: conservation and divergence of Hedgehog pathways from Drosophila to vertebrates. Development. 2006, 133 (1): 3-14. 10.1242/dev.02169.CrossRefPubMed
7.
go back to reference Molly DS, Weng L, Xin SJ, Du W: Hedgehog regulates cell growth and proliferation by inducing Cyclin D and Cyclin E. Nature. 2002, 417 (6886): 299-304. 10.1038/417299a.CrossRef Molly DS, Weng L, Xin SJ, Du W: Hedgehog regulates cell growth and proliferation by inducing Cyclin D and Cyclin E. Nature. 2002, 417 (6886): 299-304. 10.1038/417299a.CrossRef
8.
go back to reference Johnson RL, Rothman AL, Xie J, Goodrich LV, Bare JW, Bonifas JM, Quinn AG, Myers RM, Cox DR, Epstein EH, Scott MP: Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science. 1996, 272 (5268): 1668-1671. 10.1126/science.272.5268.1668.CrossRefPubMed Johnson RL, Rothman AL, Xie J, Goodrich LV, Bare JW, Bonifas JM, Quinn AG, Myers RM, Cox DR, Epstein EH, Scott MP: Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science. 1996, 272 (5268): 1668-1671. 10.1126/science.272.5268.1668.CrossRefPubMed
9.
go back to reference Hahn H, Wicking C, Zaphiropoulous PG, Gailani MR, Shanley S, Chidambaram A, Vorechovsky I, Holmberg E, Unden AB, Gillies S, Negus K, Smyth I, Pressman C, Leffell DJ, Gerrard B, Goldstein AM, Dean M, Toftgard R, Chenevix-Trench G, Wainwright B, Bale AE: Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell. 1996, 85 (6): 841-851. 10.1016/S0092-8674(00)81268-4.CrossRefPubMed Hahn H, Wicking C, Zaphiropoulous PG, Gailani MR, Shanley S, Chidambaram A, Vorechovsky I, Holmberg E, Unden AB, Gillies S, Negus K, Smyth I, Pressman C, Leffell DJ, Gerrard B, Goldstein AM, Dean M, Toftgard R, Chenevix-Trench G, Wainwright B, Bale AE: Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell. 1996, 85 (6): 841-851. 10.1016/S0092-8674(00)81268-4.CrossRefPubMed
10.
go back to reference Xie JW, Murone M, Luoh SM, Ryan A, Gu Q, Zhang C, Bonifas JM, Lam CW, Hynes M, Goddard A, Rosenthal A, Epstein EH, de Sauvage FJ: Activating smoothened mutations in sporadic basal-cell carcinoma. Nature. 1998, 391 (1): 90-92.PubMed Xie JW, Murone M, Luoh SM, Ryan A, Gu Q, Zhang C, Bonifas JM, Lam CW, Hynes M, Goddard A, Rosenthal A, Epstein EH, de Sauvage FJ: Activating smoothened mutations in sporadic basal-cell carcinoma. Nature. 1998, 391 (1): 90-92.PubMed
11.
go back to reference Xie JW, Johnson RL, Zhang XL, Bare JW, Waldman FM, Cogen PH, Menon AG, Warren RS, Chen LC, Scott MP, Epstein EH: Mutations of the patched gene in several types of sporadic extracutaneous tumors. Cancer Res. 1997, 57 (12): 2369-2372.PubMed Xie JW, Johnson RL, Zhang XL, Bare JW, Waldman FM, Cogen PH, Menon AG, Warren RS, Chen LC, Scott MP, Epstein EH: Mutations of the patched gene in several types of sporadic extracutaneous tumors. Cancer Res. 1997, 57 (12): 2369-2372.PubMed
12.
go back to reference Karhadkar SS, Hallahan AR, Pritchard JI, Eberhart CG, Watkins DN, Chen JK, Cooper MK, Taipale J, Olson JM, Beachy PA: Medulloblastoma growth inhibition by hedgehog pathway blockade. Science. 2002, 297 (5586): 1559-1561. 10.1126/science.1073733.CrossRefPubMed Karhadkar SS, Hallahan AR, Pritchard JI, Eberhart CG, Watkins DN, Chen JK, Cooper MK, Taipale J, Olson JM, Beachy PA: Medulloblastoma growth inhibition by hedgehog pathway blockade. Science. 2002, 297 (5586): 1559-1561. 10.1126/science.1073733.CrossRefPubMed
13.
go back to reference Dierks C, Grbic J, Zirlik K, Beigi R, Englund NP, Guo GR, Veelken H, Engelhardt M, Mertelsmann R, Kelleher JF, Schultz P, Warmuth M: Essential role of stromally induced hedgehog signaling in B-cell malignancies. Nature Medicin. 2007, 13 (8): 944-951. 10.1038/nm1614.CrossRef Dierks C, Grbic J, Zirlik K, Beigi R, Englund NP, Guo GR, Veelken H, Engelhardt M, Mertelsmann R, Kelleher JF, Schultz P, Warmuth M: Essential role of stromally induced hedgehog signaling in B-cell malignancies. Nature Medicin. 2007, 13 (8): 944-951. 10.1038/nm1614.CrossRef
14.
go back to reference Bai LY, Chiu CF, Lin CW, Hsu NY, Lin CL, Lo WJ, Kao MC: Differential expression of Sonic hedgehog and Gli1 in hematological malignancies. Leukemia. 2008, 22 (1): 226-228. 10.1038/sj.leu.2404978.CrossRefPubMed Bai LY, Chiu CF, Lin CW, Hsu NY, Lin CL, Lo WJ, Kao MC: Differential expression of Sonic hedgehog and Gli1 in hematological malignancies. Leukemia. 2008, 22 (1): 226-228. 10.1038/sj.leu.2404978.CrossRefPubMed
15.
go back to reference Peacock CD, Wang QJ, Gesell GS, Corcoran-Schwartz IM, Jones E, Kim J, Devereux WL, Rhodes JT, Huff CA, Beachy PA, Watkins DN, Matsui W: Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma. PNAS. 2007, 104 (10): 4048-4053. 10.1073/pnas.0611682104.PubMedCentralCrossRefPubMed Peacock CD, Wang QJ, Gesell GS, Corcoran-Schwartz IM, Jones E, Kim J, Devereux WL, Rhodes JT, Huff CA, Beachy PA, Watkins DN, Matsui W: Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma. PNAS. 2007, 104 (10): 4048-4053. 10.1073/pnas.0611682104.PubMedCentralCrossRefPubMed
16.
go back to reference Hochhaus A, O'Brien SG, Guilhot F, Druker BJ, Branford S, Foroni L, Goldman JM, Müller MC, Radich JP, Rudoltz M, Mone M, Gathmann I, Hughes TP, Larson RA: IRIS Investigators. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia IRIS 6-year follow-up. Leukemia. 2009, 23 (6): 1054-1061. 10.1038/leu.2009.38.CrossRefPubMed Hochhaus A, O'Brien SG, Guilhot F, Druker BJ, Branford S, Foroni L, Goldman JM, Müller MC, Radich JP, Rudoltz M, Mone M, Gathmann I, Hughes TP, Larson RA: IRIS Investigators. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia IRIS 6-year follow-up. Leukemia. 2009, 23 (6): 1054-1061. 10.1038/leu.2009.38.CrossRefPubMed
17.
go back to reference Merante S, Oriandi E, Bernasconi P, Calatroni S, Boni M, Lazzarino M: Outcome of four patients with chronic myeloid leukemia after imatinb mesylate discontinuation. Haematologica. 2005, 90 (7): 979-981.PubMed Merante S, Oriandi E, Bernasconi P, Calatroni S, Boni M, Lazzarino M: Outcome of four patients with chronic myeloid leukemia after imatinb mesylate discontinuation. Haematologica. 2005, 90 (7): 979-981.PubMed
18.
go back to reference Chu S, Xu H, Shah NP, Snyder DS, Forman SJ, Sawyers CL, Bhatia R: Detection of BCR-ABL kinase mutations in CD34+ cells from chronic myelogenous leukemia patients in complete cytogenetic remission on imatinib mesylate treatment. Blood. 2005, 105 (5): 2093-2098. 10.1182/blood-2004-03-1114.CrossRefPubMed Chu S, Xu H, Shah NP, Snyder DS, Forman SJ, Sawyers CL, Bhatia R: Detection of BCR-ABL kinase mutations in CD34+ cells from chronic myelogenous leukemia patients in complete cytogenetic remission on imatinib mesylate treatment. Blood. 2005, 105 (5): 2093-2098. 10.1182/blood-2004-03-1114.CrossRefPubMed
19.
go back to reference Barnes DJ, Melo JV: Primitive, quiescent and difficult to kill: the role of non-proliferating stem cells in chronic myeloid leukemia. Cell Cycle. 2006, 5 (24): 2862-2866. 10.4161/cc.5.24.3573.CrossRefPubMed Barnes DJ, Melo JV: Primitive, quiescent and difficult to kill: the role of non-proliferating stem cells in chronic myeloid leukemia. Cell Cycle. 2006, 5 (24): 2862-2866. 10.4161/cc.5.24.3573.CrossRefPubMed
20.
go back to reference Hu Y, Swerdlow S, Duffy TM, Weinmann R, Lee FY, Li S: Targeting multiple kinase pathways in leukemic progenitors and stem cells is essential for improved treatment of Ph+ leukemia in mice. PNAS. 2006, 103 (45): 16870-16875. 10.1073/pnas.0606509103.PubMedCentralCrossRefPubMed Hu Y, Swerdlow S, Duffy TM, Weinmann R, Lee FY, Li S: Targeting multiple kinase pathways in leukemic progenitors and stem cells is essential for improved treatment of Ph+ leukemia in mice. PNAS. 2006, 103 (45): 16870-16875. 10.1073/pnas.0606509103.PubMedCentralCrossRefPubMed
21.
go back to reference Pierce A, Smith DL, Jakobsen LV, Whetton AD, Spooncer E: The specific enhancement of interferon alpha induced growth inhibition by BCR/ABL only occurs in multipotent cells. Hematology Journal. 2001, 2 (4): 257-264. 10.1038/sj.thj.6200114.CrossRefPubMed Pierce A, Smith DL, Jakobsen LV, Whetton AD, Spooncer E: The specific enhancement of interferon alpha induced growth inhibition by BCR/ABL only occurs in multipotent cells. Hematology Journal. 2001, 2 (4): 257-264. 10.1038/sj.thj.6200114.CrossRefPubMed
22.
go back to reference The Italian Cooperative Study Group on Chronic Myeloid Leukemia: Interferon Alfa-2a as compared with conventional chemotherapy for the treatment of chronic myeloid leukemia. The New England Journal of Medicine. 1994, 330 (12): 820-825. 10.1056/NEJM199403243301204.CrossRef The Italian Cooperative Study Group on Chronic Myeloid Leukemia: Interferon Alfa-2a as compared with conventional chemotherapy for the treatment of chronic myeloid leukemia. The New England Journal of Medicine. 1994, 330 (12): 820-825. 10.1056/NEJM199403243301204.CrossRef
23.
go back to reference Bonifazi F, de Vivo A, Rosti G, Guilhot F, Guilhot J, Trabacchi E, Hehlmann R, Hochhaus A, Shepherd PC, Steegmann JL, Kluin-Nelemans HC, Thaler J, Simonsson B, Louwagie A, Reiffers J, Mahon FX, Montefusco E, Alimena G, Hasford J, Richards S, Saglio G, Testoni N, Martinelli G, Tura S, Baccarani M, Europena Study Group on Interferon in Chronic Myeloid Leukemia; Italian Cooperative Study Group on CML; France Intergroup of CML; German CML Study Group; UK Medical Research Council Working Party on CML: Chronic myeloid leukemia and interferon -alpha: a study of complete cytogenetic esponders. Blood. 2001, 98 (10): 3074-3081. 10.1182/blood.V98.10.3074.CrossRefPubMed Bonifazi F, de Vivo A, Rosti G, Guilhot F, Guilhot J, Trabacchi E, Hehlmann R, Hochhaus A, Shepherd PC, Steegmann JL, Kluin-Nelemans HC, Thaler J, Simonsson B, Louwagie A, Reiffers J, Mahon FX, Montefusco E, Alimena G, Hasford J, Richards S, Saglio G, Testoni N, Martinelli G, Tura S, Baccarani M, Europena Study Group on Interferon in Chronic Myeloid Leukemia; Italian Cooperative Study Group on CML; France Intergroup of CML; German CML Study Group; UK Medical Research Council Working Party on CML: Chronic myeloid leukemia and interferon -alpha: a study of complete cytogenetic esponders. Blood. 2001, 98 (10): 3074-3081. 10.1182/blood.V98.10.3074.CrossRefPubMed
24.
go back to reference Cheng XL, Sumin C, Nonggaao H, Li C, Chi S, He N, Zhang X, Guicherit O, Wagner R, Tyring S, Xie J: IFNα induces Fas expression and apoptosis in hedgehog pathway activated BCC cells through inhibiting Ras-Erk signaling. Oncogene. 2004, 23 (8): 1608-1617. 10.1038/sj.onc.1207273.CrossRef Cheng XL, Sumin C, Nonggaao H, Li C, Chi S, He N, Zhang X, Guicherit O, Wagner R, Tyring S, Xie J: IFNα induces Fas expression and apoptosis in hedgehog pathway activated BCC cells through inhibiting Ras-Erk signaling. Oncogene. 2004, 23 (8): 1608-1617. 10.1038/sj.onc.1207273.CrossRef
Metadata
Title
Activation of the hedgehog pathway in chronic myelogeneous leukemia patients
Authors
Bing Long
Huanling Zhu
Cuixia Zhu
Ting Liu
Wentong Meng
Publication date
01-12-2011
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2011
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/1756-9966-30-8

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