BACKGROUND: Inhibition of BCR-ABL tyrosine kinase activity has evolved as a mainstay of therapy for patients with chronic myeloid leukemia. However, a fraction of leukemic cells persists under targeted therapy and can lead to disease progression on cessation of treatment. DESIGN AND METHODS: We analyzed bone marrow progenitor cells with the side population phenotype, and characterized the role of the intracellular ABC transporter A3 in imatinib detoxification. RESULTS: BCR-ABL-positive leukemic cells contribute to the side population cell compartment in untreated patients. Such leukemic side population cells, as well as CD34-positive progenitors from chronic myeloid leukemia samples, strongly express the intracellular ABCA3. Functionally, ABCA3 levels are critical for the susceptibility of chronic myeloid leukemia blast cell lines to specific BCR-ABL inhibition by imatinib. The transporter is localized in the limiting membrane of lysosomes and multivesicular bodies, and intracellular [(14)C]-labeled imatinib accumulates in such organelles. The lysosomal storage capacity increases with ABCA3 expression, thus regulating imatinib sequestration. CONCLUSIONS: The intracellular ABC transporter A3 is expressed in chronic myeloid leukemia progenitor cells and may contribute to intrinsic imatinib resistance by facilitating lysosomal sequestration in chronic myeloid leukemia cells.
BACKGROUND: Inhibition of BCR-ABL tyrosine kinase activity has evolved as a mainstay of therapy for patients with chronic myeloid leukemia. However, a fraction of leukemic cells persists under targeted therapy and can lead to disease progression on cessation of treatment. DESIGN AND METHODS: We analyzed bone marrow progenitor cells with the side population phenotype, and characterized the role of the intracellular ABC transporter A3 in imatinib detoxification. RESULTS:BCR-ABL-positive leukemic cells contribute to the side population cell compartment in untreated patients. Such leukemic side population cells, as well as CD34-positive progenitors from chronic myeloid leukemia samples, strongly express the intracellular ABCA3. Functionally, ABCA3 levels are critical for the susceptibility of chronic myeloid leukemia blast cell lines to specific BCR-ABL inhibition by imatinib. The transporter is localized in the limiting membrane of lysosomes and multivesicular bodies, and intracellular [(14)C]-labeled imatinib accumulates in such organelles. The lysosomal storage capacity increases with ABCA3 expression, thus regulating imatinib sequestration. CONCLUSIONS: The intracellular ABC transporter A3 is expressed in chronic myeloid leukemia progenitor cells and may contribute to intrinsic imatinib resistance by facilitating lysosomal sequestration in chronic myeloid leukemia cells.
Authors: Susan M Graham; Heather G Jørgensen; Elaine Allan; Charlie Pearson; Michael J Alcorn; Linda Richmond; Tessa L Holyoake Journal: Blood Date: 2002-01-01 Impact factor: 22.113
Authors: S Zhou; J D Schuetz; K D Bunting; A M Colapietro; J Sampath; J J Morris; I Lagutina; G C Grosveld; M Osawa; H Nakauchi; B P Sorrentino Journal: Nat Med Date: 2001-09 Impact factor: 53.440
Authors: Surafel Mulugeta; Joseph M Gray; Kathleen L Notarfrancesco; Linda W Gonzales; Michael Koval; Sheldon I Feinstein; Philip L Ballard; Aron B Fisher; Henry Shuman Journal: J Biol Chem Date: 2002-04-08 Impact factor: 5.157
Authors: Kevin Norwood; Rui-Yu Wang; Charlotte Hirschmann-Jax; Michael Andreeff; Malcolm K Brenner; Margaret A Goodell; Gerald G Wulf Journal: Leuk Res Date: 2004-03 Impact factor: 3.156
Authors: Ravi Bhatia; Melissa Holtz; Ning Niu; Rachel Gray; David S Snyder; Charles L Sawyers; Daniel A Arber; Marilyn L Slovak; Stephen J Forman Journal: Blood Date: 2003-02-06 Impact factor: 22.113
Authors: B Chapuy; R Koch; U Radunski; S Corsham; N Cheong; N Inagaki; N Ban; D Wenzel; D Reinhardt; A Zapf; S Schweyer; F Kosari; W Klapper; L Truemper; G G Wulf Journal: Leukemia Date: 2008-05-08 Impact factor: 11.528
Authors: Stephen G O'Brien; François Guilhot; Richard A Larson; Insa Gathmann; Michele Baccarani; Francisco Cervantes; Jan J Cornelissen; Thomas Fischer; Andreas Hochhaus; Timothy Hughes; Klaus Lechner; Johan L Nielsen; Philippe Rousselot; Josy Reiffers; Giuseppe Saglio; John Shepherd; Bengt Simonsson; Alois Gratwohl; John M Goldman; Hagop Kantarjian; Kerry Taylor; Gregor Verhoef; Ann E Bolton; Renaud Capdeville; Brian J Druker Journal: N Engl J Med Date: 2003-03-13 Impact factor: 91.245
Authors: Sergey Shulenin; Lawrence M Nogee; Tarmo Annilo; Susan E Wert; Jeffrey A Whitsett; Michael Dean Journal: N Engl J Med Date: 2004-03-25 Impact factor: 91.245
Authors: Jean-Pierre Gillet; Anna Maria Calcagno; Sudhir Varma; Miguel Marino; Lisa J Green; Meena I Vora; Chirayu Patel; Josiah N Orina; Tatiana A Eliseeva; Vineet Singal; Raji Padmanabhan; Ben Davidson; Ram Ganapathi; Anil K Sood; Bo R Rueda; Suresh V Ambudkar; Michael M Gottesman Journal: Proc Natl Acad Sci U S A Date: 2011-11-08 Impact factor: 11.205
Authors: Thiha Aung; Bjoern Chapuy; Daniel Vogel; Dirk Wenzel; Martin Oppermann; Marlen Lahmann; Toni Weinhage; Kerstin Menck; Timo Hupfeld; Raphael Koch; Lorenz Trümper; Gerald G Wulf Journal: Proc Natl Acad Sci U S A Date: 2011-08-25 Impact factor: 11.205
Authors: Ha-Won Jeong; Wei Cui; Youyang Yang; Jiayun Lu; Jie He; Ailing Li; David Song; Ye Guo; Bee H Liu; Li Chai Journal: PLoS One Date: 2011-04-19 Impact factor: 3.240
Authors: Thomas O'Hare; Christopher A Eide; Anupriya Agarwal; Lauren T Adrian; Matthew S Zabriskie; Ryan J Mackenzie; Dorian H Latocha; Kara J Johnson; Huihong You; Jenny Luo; Steven M Riddle; Bryan D Marks; Kurt W Vogel; Dennis R Koop; John Apgar; Jeffrey W Tyner; Michael W Deininger; Brian J Druker Journal: Cancer Res Date: 2013-04-10 Impact factor: 12.701