Activity of tyrosine kinase inhibitors against human NUP214-ABL1-positive T cell malignancies

Quintás‐Cardama, Alfonso; Tong, Weigang; Manshouri, Taghi; Vega, Francisco; Lennon, Patrick A.; Cools, Jan; Gilliland, D. Gary; Lee, F; Cortes, Jorge; Kantarjian, Hagop M.; Garcia‐Manero, Guillermo

doi:10.1038/leu.2008.80

Cited by 89 publications

(63 citation statements)

References 28 publications

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“…24,25 In addition, NUP214-ABL1 lacks a direct binding site for the adaptor protein GRB2 that was shown to contribute to transformation and leukemogenesis of BCR-ABL1 and TEL-ABL1 12,14,15,26 and lacks phosphorylation of its activation loop (Tyr-412). 24,27 Finally, NUP214-ABL1 has attenuated transforming capacity as compared with BCR-ABL1 and preferentially transforms T cells, which is in agreement with its unique occurrence in T-cell ALL. 24 On the basis of these observations, we have performed a thorough comparison of NUP214-ABL1 and BCR-ABL1 to highlight the unique biochemical properties of NUP214-ABL1 and to gain mechanistic insight in the different disease phenotypes caused by these two oncoproteins.…”

Section: Introductionsupporting

confidence: 58%

Intrinsic differences between the catalytic properties of the oncogenic NUP214-ABL1 and BCR-ABL1 fusion protein kinases

Keersmaecker¹,

Versele²,

Cools³

et al. 2008

Leukemia

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The NUP214-ABL1 fusion kinase has recently been identified in 6% of patients with T-cell acute lymphoblastic leukemia. In contrast to the more common oncogenic ABL1 fusion BCR-ABL1, NUP214-ABL1 localizes to the nuclear pore complexes and has attenuated transforming properties in hematopoietic cells and in mouse bone marrow transplant models. We have performed a thorough biochemical comparative analysis of NUP214-ABL1 and BCR-ABL1 and show that, despite their common tyrosine kinase domain, the two fusion proteins differ in many critical catalytic properties. NUP214-ABL1 has lower in vitro tyrosine kinase activity, which is in agreement with the absence of phosphorylation on its activation loop. NUP214-ABL1 was more sensitive to imatinib (Glivec) than BCR-ABL1 in vitro and in cells, indicating a different activation state and conformation of the two ABL1 fusion kinases. Using a peptide array, we identified differences in the spectrum and efficiency of substrate peptide phosphorylation and a differential involvement of Src kinases in downstream signaling. These results clearly indicate that different fusion partners of the same kinase can determine not only localization, but also critical functional properties of the enzyme such as inhibitor sensitivity and substrate preference, with subsequent differences in downstream signaling effectors and likely consequences in disease pathogenesis.

show abstract

Section: Introductionsupporting

confidence: 58%

Intrinsic differences between the catalytic properties of the oncogenic NUP214-ABL1 and BCR-ABL1 fusion protein kinases

Keersmaecker¹,

Versele²,

Cools³

et al. 2008

Leukemia

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“…Related ABL1 rearrangements present in T-ALL include EML1-ABL1 and ETV6-ABL1 (109,110). Notably, preclinical testing of small-molecule tyrosine kinase inhibitors (developed for the treatment of BCR-ABL1-positive leukemias) in NUP214-ABL1 tumors support the hypothesis that ABL1 inhibition may be used as a targeted therapy in these patients (111,112).…”

Section: Genetic Alterations In Signal Transduction Pathwaysmentioning

confidence: 78%

“…In addition, the presence of activated kinase oncoproteins in a subset of T-ALLs may offer an additional opportunity for molecularly tailored therapies. Given the efficacy of ABL1 kinase inhibitors for the treatment of BCR-ABL1-positive leukemias and the sensitivity of NUP214-ABL1 to these inhibitors (108,111,124), NUP214-ABL1-positive T-ALL patients may benefit from the inclusion of ABL1 inhibitors in their treatment schemes. Similarly, patients with activating JAK1 (119), JAK3 (33), or IL7R mutations (120, 121) might benefit from the JAK/STAT inhibitors currently under development for the treatment of myeloproliferative disorders.…”

Section: The Challenge Ahead: Predicting Prognosis and Developing Molmentioning

confidence: 99%

The molecular basis of T cell acute lymphoblastic leukemia

Vlierberghe¹,

Ferrando²

2012

J. Clin. Invest.

433

395

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T cell acute lymphoblastic leukemias (T-ALLs) arise from the malignant transformation of hematopoietic progenitors primed toward T cell development, as result of a multistep oncogenic process involving constitutive activation of NOTCH signaling and genetic alterations in transcription factors, signaling oncogenes, and tumor suppressors. Notably, these genetic alterations define distinct molecular groups of T-ALL with specific gene expression signatures and clinicobiological features. This review summarizes recent advances in our understanding of the molecular genetics of T-ALL.

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“…Episomal amplification of NUP214-ABL1 has been reported in T-cell malignancies and this cell type has also shown sensitivity to dasatinib monotherapy (47,48). Although the NUP214-ABL1 translocation is rare in B-cell malignancies, it has been previously reported in Ph-like ALL (12).…”

Section: All-77-py-tksmentioning

confidence: 98%

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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Activity of tyrosine kinase inhibitors against human NUP214-ABL1-positive T cell malignancies

Cited by 89 publications

References 28 publications

Intrinsic differences between the catalytic properties of the oncogenic NUP214-ABL1 and BCR-ABL1 fusion protein kinases

Intrinsic differences between the catalytic properties of the oncogenic NUP214-ABL1 and BCR-ABL1 fusion protein kinases

The molecular basis of T cell acute lymphoblastic leukemia

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

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