Maturation of the Thalidomystery

Yossi Cohen^1, , Odit Gutwein¹, Osnat Garach-Jehoshua², Adina Bar-Chaim³ and Abraham Kornberg¹

¹Department of Hematology, Affiliated to Sackler Faculty of Medicine, Tel Aviv University, Israel

²Hematology Laboratory, Affiliated to Sackler Faculty of Medicine, Tel Aviv University, Israel

³Chemistry Department, Assaf Harofeh Medical Center, Zerifin, Israel

Cite this paper:
Yossi Cohen, Odit Gutwein, Osnat Garach-Jehoshua, Adina Bar-Chaim and Abraham Kornberg. Maturation of the Thalidomystery. International Journal of Hematological Disorders. 2014; 1(1A):1-6. doi: 10.12691/ijhd-1-1A-1

Abstract

Despite years of investigations, the mechanism of action of thalidomide and its derivatives is still unsolved. Recently we elaborated on the basis of the current literature data, including x-ray images of thalidomide victims, a hypothesis that premature differentiation of developing limb elements underlies the teratogenic effects of thalidomide and may also account for the antitumoral activity of the IMiDs. To examine the feasibility of this theory, we searched within gene expression profile datasets, which analyzed the changes induced by the IMiDs in myeloma cells, for supportive evidence. As expected, our analysis revealed a reproducible upregulation of a cluster of differentiating genes induced after either in-vivo or in-vitro treatment of the tumor-cells with thalidomide/ lenalidomide. This finding debates the long standing dogma that ascribed the teratogenic effect of thalidomide to apoptosis or toxic injury to limb bud mesenchyme/blood-vessels and places the IMiDs in line with differentiating teratogens like retinoids and related compounds.

Keywords:
Thalidomide lenalidomide dexamethasone gene expression profile PLSCR1 differentiation

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References:

[1]	Cohen Y. The mechanism of action of novel antimyeloma agents and newer therapeutic strategies. In: Steve Holt Multiple Myeloma: Risk Factors, Diagnosis and Treatment. Nova Publishers Ltd: USA 2014 (in press).
[2]	Yaccoby S, Johnson CL, Mahaffey SC, Wezeman MJ, Barlogie B, et al (2002) Antimyeloma efficacy of thalidomide in the SCID-hu model. Blood 100: 4162-4168.
[3]	Burington B, Barlogie B, Zhan F, Crowley J, Shaughnessy JD Jr (2008) Tumor cell gene expression changes following short-term in vivo exposure to single agent chemotherapeutics are related to survival in multiple myeloma. Clin Cancer Res 14: 4821-4829.
[4]	Zhao KW, Li X, Zhao Q, Huang Y, Li D, et al (2004) Protein kinase Cdelta mediates retinoic acid and phorbol myristate acetate-induced phospholipid scramblase 1 gene expression: its role in leukemic cell differentiation. Blood 104: 3731-3738.
[5]	Chen Y, Hui H, Yang H, Zhao K, Qin Y, et al (2013) Wogonoside induces cell cycle arrest and differentiation by affecting expression and subcellular localization of PLSCR1 in AML cells. Blood 121: 3682-3691.
[6]	Zhang K, Guo QL, You QD, Yang Y, Zhang HW, et al (2008) Wogonin induces the granulocytic differentiation of human NB4 promyelocytic leukemia cells and up-regulates phospholipid scramblase 1 gene expression. Cancer Sci 99: 689-695.
[7]	Qin Y1, Li Z, Chen Y, Hui H, Sun Y, et al (2012) III-10, a newly synthesized flavonoid, induced differentiation of human U937 leukemia cells via PKCδ activation. Eur J Pharm Sci 45: 648-656.
[8]	Damek-Poprawa M, Golub E, Otis L, Harrison G, Phillips C, et al (2006) Chondrocytes utilize a cholesterol-dependent lipid translocator to externalize phosphatidylserine. Biochemistry 45: 3325-3336.
[9]	Mao WG, Liu ZL, Chen R, Li AP, Zhou JW (2006) JWA is required for the antiproliferative and pro-apoptotic effects of all-trans retinoic acid in Hela cells. Clin Exp Pharmacol Physiol 33: 816-824.
[10]	Zhou J, Ye J, Zhao X, Li A, Zhou J (2008) JWA is required for arsenic trioxide induced apoptosis in HeLa and MCF-7 cells via reactive oxygen species and mitochondria linked signal pathway. Toxicol Appl Pharmacol 230: 33-40.
[11]	Huang S, Shen Q, Mao WG, Li AP, Ye J, et al (2006) JWA, a novel signaling molecule, involved in all-trans retinoic acid induced differentiation of HL-60 cells. J Biomed Sci 13: 357-371.
[12]	Hirvonen MJ, Mulari MT, Büki KG, Vihko P, Härkönen PL, et al (2012) Rab13 is upregulated during osteoclast differentiation and associates with small vesicles revealing polarized distribution in resorbing cells. J Histochem Cytochem 60: 537-549.
[13]	Arnold MA, Kim Y, Czubryt MP, Phan D, McAnally J, et al (2007) MEF2C transcription factor controls chondrocyte hypertrophy and bone development. Dev. Cell 12: 377-389.
[14]	Nigten J, Breems-de Ridder MC, Erpelinck-Verschueren CA, Nikoloski G, van der Reijden BA, et al (2005) ID1 and ID2 are retinoic acid responsive genes and induce a G0/G1 accumulation in acute promyelocytic leukemia cells. Leukemia 19: 799-805.
[15]	Sakata-Goto T, Takahashi K, Kiso H, Huang B, Tsukamoto H, et al (2012) Id2 controls chondrogenesis acting downstream of BMP signaling during maxillary morphogenesis. Bone 50: 69-78.
[16]	Shim JH, Shin DW, Lee TR, Kang HH, Jin SH, et al (2012) The retinoic acid-induced up-regulation of insulin-like growth factor 1 and 2 is associated with prolidase-dependent collagen synthesis in UVA-irradiated human dermal equivalents. J. Dermatol. Sci 66: 51-59.
[17]	Weidtkamp-Peters S, Lenser T, Negorev D, Gerstner N, Hofmann TG, et al (2008) Dynamics of component exchange at PML nuclear bodies. J Cell Sci 121: 2731-2743.
[18]	Yuwaraj S, Ding J, Liu M, Marsden PA, Levy, G. A (2001) Genomic characterization, localization, and functional expression of FGL2, the human gene encoding fibroleukin: a novel human procoagulant. Genomics 71: 330-338.
[19]	Matsui W, Wang Q, Barber JP, Brennan S, Smith BD, et al (2008) Clonogenic multiple myeloma progenitors, stem cell properties, and drug resistance. Cancer Res 58: 190-197.
[20]	Trus MR, Yang L, Suarez Saiz F, Bordeleau L, Jurisica I, et al (2005) The histone deacetylase inhibitor valproic acid alters sensitivity towards all trans retinoic acid in acute myeloblastic leukemia cells. Leukemia 19: 1161-1168.
[21]	Bortolin-Cavaillé ML, Cavaillé J (2012) The SNORD115 (H/MBII-52) and SNORD116 (H/MBII-85) gene clusters at the imprinted Prader-Willi locus generate canonical box C/D snoRNAs. Nucleic Acids Res 40: 6800-6807.
[22]	Lebrin F, Srun S, Raymond K, Martin S, van den Brink S, et al (2010) Thalidomide stimulates vessel maturation and reduces epistaxis in individuals with hereditary hemorrhagic telangiectasia. Nat. Med 16: 420-428.
[23]	Cohen Y, Garach-Jehoshua O, Bar-Chaim A, Kornberg A (2012) Niche-modulated and niche-modulating genes in bone marrow cells. Blood Cancer J 2: e97.
[24]	Cohen Y, Gutwein O, Garach-Jehoshua O, Bar-Haim A, Kornberg A (2014) The proliferation arrest of primary tumor cells out-of-niche is associated with widespread downregulation of mitotic and transcriptional genes. Hematology 19: 286-292.