Chronic myeloid leukemia |
K562 |
IRS1 is constitutively phosphorylated on tyrosine residues and associates with BCR-ABL1. |
IP, WB |
Traina et al.(6868. Traina F, Carvalheira JB, Saad MJ, Costa FF, Saad ST. BCR-ABL binds to IRS-1 and IRS-1 phosphorylation is inhibited by imatinib in K562 cells. FEBS Lett. 2003;535(1-3):17-22, http://dx.doi.org/10.1016/S0014-5793(02)03845-0. http://dx.doi.org/10.1016/S0014-5793(02)...
) |
Chronic myeloid leukemia |
K562 |
IRS1 silencing reduces cell proliferation and clonogenicity and inhibits mTOR/Akt and MAPK activation. |
shRNA-lentiviral delivery |
Machado-Neto et al. (6969. Machado-Neto JA, Favaro P, Lazarini M, Costa FF, Olalla Saad ST, Traina F. Knockdown of insulin receptor substrate 1 reduces proliferation and downregulates Akt/mTOR and MAPK pathways in K562 cells. Biochim Biophys Acta. 2011;1813(8):1404-11, http://dx.doi.org/10.1016/j.bbamcr.2011.04.002. http://dx.doi.org/10.1016/j.bbamcr.2011....
) |
Chronic myeloid leukemia |
K562 and LAMA-84 |
IRS1 and IRS2 silencing reduces cell viability and metabolism. |
siRNA and transfection |
Zhao et al. (7070. Zhao H, Liu F, Jia R, Chang H, Li H, Miao M, et al. MiR-570 inhibits cell proliferation and glucose metabolism by targeting IRS1 and IRS2 in human chronic myelogenous leukemia. Iran J Basic Med Sci. 2017;20(5):481-8.) |
Philadelphia-negative myeloproliferative neoplasm |
HEL, U937 and primary samples |
IRS2 is associated with the JAK2V617F mutation and induces survival in JAK2V617F-positive cells. NT157 reduces the viability of primary cells from MPN patients. |
IP, WB and shRNA-lentiviral delivery |
de Melo Campos et al. (7676. de Melo Campos P, Machado-Neto JA, Eide CA, Savage SL, Scopim-Ribeiro R, da Silva Souza Duarte A, et al. IRS2 silencing increases apoptosis and potentiates the effects of ruxolitinib in JAK2V617F-positive myeloproliferative neoplasms. Oncotarget. 2016;7(6):6948-59.) |
Acute myeloid leukemia |
Primary samples |
IRS1 mediates resistance to PI3K signaling inhibition. |
WB |
Bertacchini et al. (8585. Bertacchini J, Guida M, Accordi B, Mediani L, Martelli AM, Barozzi P, et al. Feedbacks and adaptive capabilities of the PI3K/Akt/mTOR axis in acute myeloid leukemia revealed by pathway selective inhibition and phosphoproteome analysis. Leukemia. 2014;28(11):2197-205, http://dx.doi.org/10.1038/leu.2014.123. http://dx.doi.org/10.1038/leu.2014.123...
) |
Acute myeloid leukemia |
Primary samples |
IRS2 is upregulated by autocrine activation of IGF1/IGF1R signaling upon Akt/mTOR inhibitor treatment. |
WB |
Tamburini et al. (8383. Tamburini J, Chapuis N, Bardet V, Park S, Sujobert P, Willems L, et al. Mammalian target of rapamycin (mTOR) inhibition activates phosphatidylinositol 3-kinase/Akt by up-regulating insulin-like growth factor-1 receptor signaling in acute myeloid leukemia: rationale for therapeutic inhibition of both pathways. Blood. 2008;111(1):379-82, http://dx.doi.org/10.1182/blood-2007-03-080796. http://dx.doi.org/10.1182/blood-2007-03-...
) |
Acute myeloid leukemia |
Primary samples |
IRS1 phosphorylation on serine 1101 is a biological marker of p53 pathway deregulation. |
Proteomics and network analyses |
Quintás-Cardama et al. (8787. Quintas-Cardama A, Hu C, Qutub A, Qiu YH, Zhang X, Post SM, et al. p53 pathway dysfunction is highly prevalent in acute myeloid leukemia independent of TP53 mutational status. Leukemia. 2017;31(6):1296-305, http://dx.doi.org/10.1038/leu.2016.350. http://dx.doi.org/10.1038/leu.2016.350...
) |
Myelodysplastic syndrome |
Primary samples |
IRS2 is downregulated and is associated with an increased severity of cytopenia in MDS patients. |
qPCR |
Machado-Neto et al. (4040. Machado-Neto JA, Favaro P, Lazarini M, da Silva Santos Duarte A, Archangelo LF, Lorand-Metze I, et al. Downregulation of IRS2 in myelodysplastic syndrome: a possible role in impaired hematopoietic cell differentiation. Leuk Res. 2012;36(7):931-5, http://dx.doi.org/10.1016/j.leukres.2012.03.002. http://dx.doi.org/10.1016/j.leukres.2012...
) |
Myelodysplastic syndrome |
Primary samples |
IRS2 is downregulated in bone marrow mononuclear cells from MDS patients compared with cells from healthy donors. |
cDNA microarray |
Bar et al. (8888. Bar M, Stirewalt D, Pogosova-Agadjanyan E, Wagner V, Gooley T, Abbasi N, et al. Gene expression patterns in myelodyplasia underline the role of apoptosis and differentiation in disease initiation and progression. Transl Oncogenomics. 2008;3:137-49.) |
Acute lymphoblastic leukemia |
Jurkat, MOLT4, Raji, Namalwa and primary samples |
IRS1 is highly expressed in ALL cell lines and primary samples. Nuclear IRS1 associates with β-catenin and activates β-catenin signaling. |
qPCR, WB and IP |
Fernandes et al. (8989. Fernandes JC, Rodrigues Alves AP, Machado-Neto JA, Scopim-Ribeiro R, Fenerich BA, da Silva FB, et al. IRS1/beta-Catenin Axis Is Activated and Induces MYC Expression in Acute Lymphoblastic Leukemia Cells. J Cell Biochem. 2017;118(7):1774-81, http://dx.doi.org/10.1002/jcb.25845. http://dx.doi.org/10.1002/jcb.25845...
) |
Acute lymphoblastic leukemia |
CCRF-CEM, NALM6 and REH |
The activation of the IGF1R/IRS1 axis is a determinant of pro- or antiapoptotic responses to AMPK activators. |
WB and cell viability assays |
Leclerc et al. (9191. Leclerc GM, Leclerc GJ, Fu G, Barredo JC. AMPK-induced activation of Akt by AICAR is mediated by IGF-1R dependent and independent mechanisms in acute lymphoblastic leukemia. J Mol Signal. 2010;5:15, http://dx.doi.org/10.1186/1750-2187-5-15. http://dx.doi.org/10.1186/1750-2187-5-15...
) |
Acute lymphoblastic leukemia |
Primary samples |
IRS1 expression negatively correlates with survival, independent of age and leukocyte count at diagnosis. |
cDNA Microarray |
Juric et al. (9292. Juric D, Lacayo NJ, Ramsey MC, Racevskis J, Wiernik PH, Rowe JM, et al. Differential gene expression patterns and interaction networks in BCR-ABL-positive and -negative adult acute lymphoblastic leukemias. J Clin Oncol. 2007;25(11):1341-9, http://dx.doi.org/10.1200/JCO.2006.09.3534. http://dx.doi.org/10.1200/JCO.2006.09.35...
) |
Acute lymphoblastic leukemia |
Primary samples |
IRS1 is a biomarker for the response to the multitarget tyrosine kinase inhibitor GZD824. |
WB and cell viability assays |
Ye et al. (9393. Ye W, Jiang Z, Lu X, Ren X, Deng M, Lin S, et al. GZD824 suppresses the growth of human B cell precursor acute lymphoblastic leukemia cells by inhibiting the SRC kinase and PI3K/AKT pathways. Oncotarget. 2017;8(50):87002-15.) |
Acute lymphoblastic leukemia |
Primary samples |
IRS4 is translocated, overexpressed and mutated in ALL patients. |
MC, FISH, WB and DNA sequencing |
Karrman et al. (9494. Karrman K, Kjeldsen E, Lassen C, Isaksson M, Davidsson J, Andersson A, et al. The t(X;7)(q22;q34) in paediatric T-cell acute lymphoblastic leukaemia results in overexpression of the insulin receptor substrate 4 gene through illegitimate recombination with the T-cell receptor beta locus. Br J Haematol. 2009;144(4):546-51, http://dx.doi.org/10.1111/j.1365-2141.2008.07453.x. http://dx.doi.org/10.1111/j.1365-2141.20...
)Kang et al. (9595. Kang DH, Kim SH, Jun JW, Lee YW, Shin HB, Ahn JY, et al. Simultaneous translocation of both TCR Loci (14q11) with rare partner loci (Xq22 and 12p13) in a case of T-lymphoblastic leukemia. Ann Lab Med. 2012;32(3):220-4, http://dx.doi.org/10.3343/alm.2012.32.3.220. http://dx.doi.org/10.3343/alm.2012.32.3....
)Karrman et al. (9696. Karrman K, Isaksson M, Paulsson K, Johansson B. The insulin receptor substrate 4 gene (IRS4) is mutated in paediatric T-cell acute lymphoblastic leukaemia. Br J Haematol. 2011;155(4):516-9, http://dx.doi.org/10.1111/j.1365-2141.2011.08709.x. http://dx.doi.org/10.1111/j.1365-2141.20...
) |
Chronic lymphocytic leukemia |
Primary samples |
IGF1R/IRS signaling is activated and promotes survival. |
WB, cell viability assays and xenograft models |
Yaktapour et al. (9797. Yaktapour N, Ubelhart R, Schuler J, Aumann K, Dierks C, Burger M, et al. Insulin-like growth factor-1 receptor (IGF1R) as a novel target in chronic lymphocytic leukemia. Blood. 2013;122(9):1621-33, http://dx.doi.org/10.1182/blood-2013-02-484386. http://dx.doi.org/10.1182/blood-2013-02-...
) |
Plasma cell neoplasms |
Murine primary tumors |
The activation of the IGF1R/IRS2/PI3K/p70S6K axis is important in the development of plasma cell tumors. |
Transfection and allograft models |
Li et al. (9898. Li W, Hyun T, Heller M, Yam A, Flechner L, Pierce JH, et al. Activation of insulin-like growth factor I receptor signaling pathway is critical for mouse plasma cell tumor growth. Cancer Res. 2000;60(14):3909-15.) |
Multiple myeloma |
ANBL-6, Brown, Delta-47, OPM-2, 8226, KMM1, H929, and MM-144 |
Activation of the IGF1R/IRS1 axis leads to the inhibition of apoptosis and the induction of cell proliferation. |
WB, cell viability assays and xenograft models |
Ge et al. (9999. Ge NL, Rudikoff S. Insulin-like growth factor I is a dual effector of multiple myeloma cell growth. Blood. 2000;96(8):2856-61.) |
Multiple myeloma |
OPM-2, 8226, MM1S and HS-Sultan |
IRS1 participates in a feedback loop that leads to mTOR inhibitor resistance. |
WB |
Shi et al. (100100. Shi Y, Yan H, Frost P, Gera J, Lichtenstein A. Mammalian target of rapamycin inhibitors activate the AKT kinase in multiple myeloma cells by up-regulating the insulin-like growth factor receptor/insulin receptor substrate-1/phosphatidylinositol 3-kinase cascade. Mol Cancer Ther. 2005;4(10):1533-40, http://dx.doi.org/10.1158/1535-7163.MCT-05-0068. http://dx.doi.org/10.1158/1535-7163.MCT-...
) |
Hairy cell leukemia |
Primary samples |
Gain-of-function mutations in IRS1 contribute to resistance to vemurafenib (BRAFV600E inhibitor). |
Deep targeted mutational and copy number analysis |
Durham et al. (102102. Durham BH, Getta B, Dietrich S, Taylor J, Won H, Bogenberger JM, et al. Genomic analysis of hairy cell leukemia identifies novel recurrent genetic alterations. Blood. 2017;130(14):1644-8.) |