Enhanced insulin‐receptor tyrosine kinase activity associated with chromosomal translocation (1;19) in a pre‐B‐cell leukemia line

Newman, Julie; Harrison, Leonard C.; Eckardt, Glenn S.; Jack, Ian

doi:10.1002/ijc.2910500328

Cited by 4 publications

(6 citation statements)

References 24 publications

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“…However, the total amount of receptor protein in tumor tissue was increased 3-to 4-fold for the insulin receptor and 2-fold for the IGF-I receptor when compared with normal tissue. These results are in accordance with observations for other carcinomas (Milazzo et al, 1992;Chung and Antoniades, 1992) and leukemia (Newman et al, 1992). On the other hand, in Burkitt-lymphoma cells, insulin-binding sites were decreased by 90% compared to lymphoblastoid cells of normal karyotype (Newman and Harrison, 1989).…”

Section: Discussionsupporting

confidence: 94%

“…Similar observations have been made with regard to insulin receptors in breast cancer (Hilf et al, 1988;Hennipman et al, 1989;Milazzo et al, 1992) and leukemia (Newman et aL, 1992). This increased specific activation of receptors, isolated from tumor tissue, was paralleled by elevated tyrosine-kinase activity toward the exogenous substrate poly(G1u:Tyr 4:l).…”

Section: Discussionsupporting

confidence: 60%

“…There is increasing evidence that insulin and IGF-I and their receptors are involved in malignant transformation: in breast (Hilf et al, 1988;Hennipman et al, 1989;Milazzo et al, 1992), gastrointestinal (Chung and Antoniades, 1992;Durrant et al, 1991;Koenuma et al, 1989) and brain tumors (Glick et aZ., 1989;Antoniades et al, 1992) as well as leukemia (Newman et al, 1992). The observation that many renal tumors contain large amounts of glycogen, phospholipids and triglycerides also suggests the involvement of insulin and/or IGF-I in renal carcinoma.…”

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confidence: 99%

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Insulin‐and insulin‐like growth‐factor‐I receptor tyrosine‐kinase activities in human renal carcinoma

Kellerer

Corleta

Mühlhöfer

et al. 1995

Intl Journal of Cancer

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We studied expression and functional characteristics of the insulin- and insulin-like-growth-factor-I (IGF-I) receptors in human renal carcinoma. Ligand-binding properties and tyrosine-kinase activity of both receptors, as well as the expression of the 2 isoforms of the human insulin receptor (HIR-A and -B) were analyzed in renal carcinoma and normal adjacent kidney tissue of 8 adult patients. Partially purified insulin- and IGF-I receptors from normal and renal cell carcinoma tissue possessed identical affinities for their ligands. Renal cell carcinoma, however, contained 3- to 4-fold more specific insulin-binding sites and 2-fold more IGF-I binding sites than adjacent normal kidney tissue. In addition, we determined the relative content of insulin/IGF-I receptor hybrids in both tissues. Renal cell carcinoma and adjacent normal tissue revealed similar amounts of insulin/IGF-I receptor hybrids, i.e., 44 +/- 8.2% of tracer IGF-I binding in normal tissue and 46 +/- 12.0% in renal cell carcinoma. When equal amounts of insulin- and IGF-I receptor protein were studied, we found significantly increased receptor autophosphorylation and elevated substrate phosphorylation in carcinoma tissue. To assess whether the differences in insulin-receptor tyrosine-kinase activity were caused by an altered pattern of insulin receptor isoform expression, we determined mRNA levels for HIR-A and -B. The 2 insulin receptor isoforms were, however, expressed in highly variable ratios in both normal and tumor tissue. Our experiments show that renal carcinoma expresses an elevated amount of insulin- and IGF-I receptor protein with increased specific autophosphorylation and tyrosine-kinase activity each. The increase of insulin-receptor tyrosine-kinase activity in renal carcinoma cannot be explained by an altered expression pattern of insulin receptor isoforms.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionsupporting

confidence: 60%

mentioning

confidence: 99%

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Insulin‐and insulin‐like growth‐factor‐I receptor tyrosine‐kinase activities in human renal carcinoma

Kellerer

Corleta

Mühlhöfer

et al. 1995

Intl Journal of Cancer

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“…Insulin is a potent growth factor, and has been shown to increase ALL cell proliferation in vivo (12). Interestingly, the common pre-B cell ALL translocation, t(1;19), may enhance insulin receptor signaling, implicating this pathway as a potential contributor to ALL pathogenesis (13). Leptin has been shown to stimulate hematopoietic progenitors and multiple leukemia cell types (14, 15), though a direct effect on ALL has not been demonstrated to our knowledge.…”

Section: Discussionmentioning

confidence: 99%

Diet-Induced Obesity Accelerates Acute Lymphoblastic Leukemia Progression in Two Murine Models

Yun

Behan

Heisterkamp

et al. 2010

Cancer Prevention Research

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Obesity is associated with an increased incidence of many cancers, including leukemia, although it is unknown whether leukemia incidence is increased directly by obesity or rather by associated genetic, lifestyle, health, or socioeconomic factors. We developed animal models of obesity and leukemia to test whether obesity could directly accelerate acute lymphoblastic leukemia (ALL) using BCR/ABL transgenic and AKR/J mice weaned onto a high-fat diet. Mice were observed until development of progressive ALL. Although obese and control BCR/ABL mice had similar median survival, older obese mice had accelerated ALL onset, implying a time-dependent effect of obesity on ALL. Obese AKR mice developed ALL significantly earlier than controls. The effect of obesity was not explained by WBC count, thymus/spleen weight, or ALL phenotype. However, obese AKR mice had higher leptin, insulin, and interleukin-6 levels than controls, and these obesity-related hormones all have potential roles in leukemia pathogenesis. In conclusion, obesity directly accelerates presentation of ALL, likely by increasing the risk of an early event in leukemogenesis. This is the first study to show that obesity can directly accelerate the progression of ALL. Thus, the observed associations between obesity and leukemia incidence are likely to be directly related to biological effects of obesity. Cancer Prev Res; 3(10); 1259-64. ©2010 AACR.

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“…2B; Supplementary Table S5). The RTK INSR has previously been reported to be involved in pre-B leukemia (34) and this kinase had the highest level of phosphorylation in this group with phosphorylation at five different sites (Y1190, Y1189, Y1185, Y1355, and Y1361). Conversely, Y842 FLT3 was unique to PAMDRM across the entire panel, whereas the Y570 site in JAK2 and the Y702 site in AXL were unique to PALLSD.…”

Section: Quantitative Analysis Of Tk Phosphotyrosine Sitesmentioning

confidence: 72%

Quantitative Phosphotyrosine Profiling of Patient-Derived Xenografts Identifies Therapeutic Targets in Pediatric Leukemia

et al. 2016

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Activating mutations in tyrosine kinases (TK) drive pediatric high-risk acute lymphoblastic leukemia (ALL) and confer resistance to standard chemotherapy. Therefore, there is urgent need to characterize dysregulated TK signaling axes in patients with ALL and identify actionable kinase targets for the development of therapeutic strategies. Here, we present the first study to quantitatively profile TK activity in xenografted patient biopsies of high-risk pediatric ALL. We integrated a quantitative phosphotyrosine profiling method with "spike-in" stable isotope labeling with amino acids in cell culture (SILAC) and quantified 1394 class I phosphorylation sites in 16 ALL xenografts. Moreover, hierarchical clustering of phosphotyrosine sites could accurately classify these leukemias into either B-or Tcell lineages with the high-risk early T-cell precursor (ETP) and Ph-like ALL clustering as a distinct group. Furthermore, we validated this approach by using specific kinase pathway inhibitors to perturb ABL1, FLT3, and JAK TK signaling in four xenografted patient samples. By quantitatively assessing the tyrosine phosphorylation status of activated kinases in xenograft models of ALL, we were able to identify and validate clinically relevant targets. Therefore, this study highlights the application and potential of phosphotyrosine profiling for identifying clinically relevant kinase targets in leukemia. Cancer Res; 76(9); 2766-77. Ó2016 AACR.

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Enhanced insulin‐receptor tyrosine kinase activity associated with chromosomal translocation (1;19) in a pre‐B‐cell leukemia line

Cited by 4 publications

References 24 publications

Insulin‐and insulin‐like growth‐factor‐I receptor tyrosine‐kinase activities in human renal carcinoma

Insulin‐and insulin‐like growth‐factor‐I receptor tyrosine‐kinase activities in human renal carcinoma

Diet-Induced Obesity Accelerates Acute Lymphoblastic Leukemia Progression in Two Murine Models

Quantitative Phosphotyrosine Profiling of Patient-Derived Xenografts Identifies Therapeutic Targets in Pediatric Leukemia

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