Table 1.

Alterations in the insulin receptor substrate (IRS) signaling pathway in hematological neoplasms.

Hematologic neoplasm	Sample/cell line	Notes	Main approaches	Publication
Chronic myeloid leukemia	K562	IRS1 is constitutively phosphorylated on tyrosine residues and associates with BCR-ABL1.	IP, WB	Traina et al.(68)
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. (69)
Chronic myeloid leukemia	K562 and LAMA-84	IRS1 and IRS2 silencing reduces cell viability and metabolism.	siRNA and transfection	Zhao et al. (70)
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. (76)
Acute myeloid leukemia	Primary samples	IRS1 mediates resistance to PI3K signaling inhibition.	WB	Bertacchini et al. (85)
Acute myeloid leukemia	Primary samples	IRS2 is upregulated by autocrine activation of IGF1/IGF1R signaling upon Akt/mTOR inhibitor treatment.	WB	Tamburini et al. (83)
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. (87)
Myelodysplastic syndrome	Primary samples	IRS2 is downregulated and is associated with an increased severity of cytopenia in MDS patients.	qPCR	Machado-Neto et al. (40)
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. (88)
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. (89)
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. (91)
Acute lymphoblastic leukemia	Primary samples	IRS1 expression negatively correlates with survival, independent of age and leukocyte count at diagnosis.	cDNA Microarray	Juric et al. (92)
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. (93)
Acute lymphoblastic leukemia	Primary samples	IRS4 is translocated, overexpressed and mutated in ALL patients.	MC, FISH, WB and DNA sequencing	Karrman et al. (94)Kang et al. (95)Karrman et al. (96)
Chronic lymphocytic leukemia	Primary samples	IGF1R/IRS signaling is activated and promotes survival.	WB, cell viability assays and xenograft models	Yaktapour et al. (97)
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. (98)
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. (99)
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. (100)
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. (102)

Abbreviations: IP, immunoprecipitation; WB, western blotting; MPN, myeloproliferative neoplasm; MDS, myelodysplastic syndrome; qPCR, quantitative polymerase chain reaction; ALL, acute lymphoblastic leukemia; MC, metaphase cytogenetics; FISH, fluorescence in situ hybridization.