The Novel BCR-ABL1 V304D Mutation Induces Pan-Tyrosine Kinase Inhibitor Resistance by a Unique Kinase Lateral Escape Mechanism and Is Associated with Very Poor Prognosis In Patients (PTS) with Chronic Myeloid Leukemia (CML).

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3402-3402
Author(s):  
Sabrina Pricl ◽  
Don L Gibbons ◽  
Paola Posocco ◽  
Erik Laurini ◽  
Maurizio Fermeglia ◽  
...  
Keyword(s):  
Binding Site ◽  
Research Funding ◽  
Poor Prognosis ◽  
Binding Pocket ◽  
Activation Loop ◽  
Wild Type ◽  
Tki Resistance ◽  
Ic50 Values ◽  
Lateral Escape ◽  
Free Energy Of Binding

Abstract Abstract 3402 We discovered a novel BCR-ABL1 mutation (V304D) in pts with CML failing imatinib by DNA expansion of specific clones followed by DNA sequencing of ≥10 clones. BCR-ABL1V304D was detected in a median of 37% (range, 20% to 80%) resistant clones from 13 (18%) of 70 imatinib-resistant pts with CML in chronic phase (CP). Pts received imatinib for a median of 35 months (range 2 to 66) at doses ≥600 mg/d. No pt achieved a cytogenetic response. Four received nilotinib: 3 had hematologic resistance and 1 progressed to blast phase (BP). All pts died with negligible response to second-line TKIs: 8/12 pts on dasatinib had disease progression and 4 responded (2 hematologic and 2 transient minor cytogenetic responses). BCR-ABL1V304D failed to induce cytokine-independence or activate Stat5 in Ba/F3 cells. Phosphorylation of CrkL and specific BCR-ABL1 substrates were detectable but diminished compared to unmutated BCR-ABL1-transduced cells. BCR-ABL1V304D failed to catalyze autophosphorylation and the catalytic domain of ABL1V304D demonstrated deficient kinase activity. Enforced expression of BCR-ABL1V304Din CML cells induced quiescence and protection from imatinib-induced apoptosis. In vitro analyses of cells from a pt in CP expressing BCR-ABL1V304D in 50% of clones failed to detect CrKL phosphorylation in the presence of normal BCR-ABL1 protein levels, suggesting that BCR-ABL1V304D encodes a kinase-deficient protein and is associated with remarkable TKI resistance and extremely poor prognosis. To determine the mechanism of resistance imposed by BCR-ABL1V304D, we modeled this mutation in water and counterions and compared it to unmutated and mutant BCR-ABL1 isoforms. We first correlated the free energy of binding (DGbind) to the corresponding IC50 (DGbind = -RT lnIC50) and calculated the difference in free energy of binding between wild-type and mutant kinases (DDGbind = DGbind(WT) – DGbind(MUT)). DGbind <0 indicates a tighter binding to a TKI of the unmutated kinase relative to the mutant kinase. A negative increase of 1.4 kcal/mol in DGbind corresponds to a decrease by a factor of 10 in the IC50 value. The DGbind (IC50) values of imatinib for wild-type, Y253H, and T315I kinases were -10.47kcal/mol (21nM), -7.45 kcal/mol (3.4mM), and -6.38 kcal/mol (21mM), similar to published experimental data (25nM, 1.8–3.9mM, and >10mM, respectively), thus validating our modeling. DGbind and IC50 values for imatinib and dasatinib against V304D are -9.86kcal/mol (59nM) and -12.27 kcal/mol (1.02nM), respectively. 3D images generated from an equilibrated frame of 10 ns molecular dynamics (MD) simulations demonstrated that the 304 position is not in direct contact with imatinib, nor does it directly alter imatinib binding. Rather, V304D disturbs the position of the regulatory αC helix (Figure1). Longer standard molecular dynamics simulations coupled with steered MD recipes indicate that V304D induces a rearrangement of the ATP/drug binding pocket and water-mediated disruption of some fundamental hydrogen bonds regulating the transition of the activation loop to a “semi-open” conformation and the apt overall conformation of the SH3-binding segment of the TK (residues K294-F311). Furthermore, a decrease in the number of total interactions causes unidirectional drug translation toward the binding site exit. Iterative simulations revealed significant ATP/inhibitor diversion with subsequent complete imatinib expulsion. Thus, the V304D-induced semi-opened conformation of the activation loop favors 1) the lateral escape of imatinib, thus increasing the rate of TKI dissociating from the kinase and 2) does not allow the passage of ATP to reach deep into the binding pocket, thus hampering tyrosine phosphorylation. A similar phenomenon is observed in the activation loop in the active conformation of the V304D kinase bound to dasatinib, which results in greater exposure to water solvent of a part of the binding site and almost complete loss of hydrophobic contacts in the opposite end of the binding site. Fig. 1 MD snapshots of Imatinib (colored sticks) bound to (top) and “escaped” from (bottom) SCTABLIV304D. The mutant residue D304 is highlighted in yellow. Note the rearrangement of the activation loop, the SH3 binding region, and the helix C, colored blue, spring green, and orange in the lower panel. Some waters and counterions are shown as colored spheres. Fig. 1. MD snapshots of Imatinib (colored sticks) bound to (top) and “escaped” from (bottom) SCTABLIV304D. The mutant residue D304 is highlighted in yellow. Note the rearrangement of the activation loop, the SH3 binding region, and the helix C, colored blue, spring green, and orange in the lower panel. Some waters and counterions are shown as colored spheres. In summary, BCR-ABL1V304D results in kinase inactivation, pan-TKI resistance mediated by a novel mechanism of lateral escape at the kinase domain, less control of protein autoinhibition via perturbation of the SH3 binding domain and very poor prognosis. Complete modeling data against a panel of novel TKIs and potential modes of overcoming this novel mechanism of resistance will be presented. Disclosures: Kantarjian: Bristol Myers Squibb: Research Funding; ARIAD: Research Funding; Nerviano: Research Funding. Cortes:Bristol Myers Squibb: Research Funding; ARIAD: Research Funding; Nerviano: Research Funding.

Northwestern Overthrusting and Related Lateral Escape During the Brasiliano Orogeny North of the Patos Lineament, Borborema Province, Northeast Brazil

1997 ◽  
Vol 39 (7) ◽  
pp. 609-620 ◽  
Author(s):  
Peter Christian Hackspacher ◽  
Elton Luiz Dantas ◽  
Benjamin Bley Brito Neves ◽  
Jean Michel Legrand
Keyword(s):  
Northeast Brazil ◽  
Borborema Province ◽  
Brasiliano Orogeny ◽  
Lateral Escape

scholarly journals Comment on “Continental collision and lateral escape deformation in the lower and upper crust: An example from Caledonide Svalbard” by N. Lyberis and G. Manby

Tectonics ◽  
2001 ◽  
Vol 20 (5) ◽  
pp. 788-793 ◽  
Author(s):  
David G. Gee ◽  
Patrik Witt-Nilsson ◽  
Åke Johansson ◽  
Fredrik J. Hellman
Keyword(s):  
Continental Collision ◽  
Upper Crust ◽  
Lateral Escape

scholarly journals Complex Economies Have a Lateral Escape from the Poverty Trap

PLoS ONE ◽  
2017 ◽  
Vol 12 (1) ◽  
pp. e0168540 ◽  
Author(s):  
Emanuele Pugliese ◽  
Guido L. Chiarotti ◽  
Andrea Zaccaria ◽  
Luciano Pietronero
Keyword(s):  
Poverty Trap ◽  
Lateral Escape

Magnetic anisotropy and X- ray diffraction study of clay minerals in the decollement horizons of the western Helvetic nappes, SW Switzerland

Clay Minerals ◽  
2001 ◽  
Vol 36 (2) ◽  
pp. 181-196 ◽  
Author(s):  
P. Dick ◽  
M. Burkhard
Keyword(s):  
Spatial Organization ◽  
Clay Mineralogy ◽  
Strain History ◽  
X Ray Diffraction ◽  
Clay Particles ◽  
X Ray ◽  
Helvetic Nappes ◽  
Magnetic Fabrics ◽  
Magnetic Lineations ◽  
Lateral Escape

AbstractAnisotropy of magnetic susceptibility (AMS) and X-ray diffraction studies on shale decollement horizons in the Western Helvetic nappes were conducted to delineate the interactions between clay particles and deformation during a non-coaxial thrusting deformation. The reorientation of magnetic lineations in the decollement horizons, from a NW—SW thrusting direction to a NE—SW oriented lateral escape, provides the opportunity to study the evolution of magnetic fabrics and clay mineralogy during a two-step deformation history. The AMS of these shales originates from paramagnetic phyllosilicate minerals: illite, phengite and chlorite. Clay mineral studies indicate that magnetic lineations parallel to the thrust directions correspond to the spatial organization of the basal planes of phengites, whereas those parallel to the lateral escape movement are caused by illites. This work indicates that the change in direction of magnetic lineations from orogenic contraction to lateral escape not only records the strain history but also the dissolution and neoformation of paramagnetic minerals.

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