Hematopoiesis and RAS-driven myeloid leukemia differentially require PI3K isoform p110α

Journal of Clinical Investigation

Volumn 124, Issue 4, 2014, Pages 1794-1809

  Gritsman, Kira ^a,b,c   Yuzugullu, Haluk ^a   Von, Thanh ^a   Yan, Howard ^a   Clayton, Linda ^a   Fritsch, Christine ^d   Maira, Sauveur Michel ^d   Hollingworth, Gregory ^e   Choi, Christine ^a   Khandan, Tulasi ^b   Paktinat, Mahnaz ^b   Okabe, Rachel O ^b   Roberts, Thomas M ^a,c   Zhao, Jean J ^a,c  

^a DANA FARBER CANCER INSTITUTE   (United States)

^b BRIGHAM AND WOMEN S HOSPITAL   (United States)

^c HARVARD MEDICAL SCHOOL   (United States)

^d NOVARTIS PHARMA AG   (Switzerland)

^e NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ARRY 438162; BUPARLISIB; FLUOROURACIL; IDELALISIB; K RAS PROTEIN; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN P110; RAS PROTEIN; STAT5 PROTEIN;

ACUTE GRANULOCYTIC LEUKEMIA; ANEMIA; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BURST FORMING UNIT E; CELL MATURATION; CELL RENEWAL; CELLULAR STRESS RESPONSE; COLONY FORMATION; CONTROLLED STUDY; ENZYME PHOSPHORYLATION; ERYTHROBLAST; EXERCISE TEST; FLOW CYTOMETRY; GENE DELETION; GRANULOCYTE; HEMATOPOIESIS; HEMATOPOIETIC STEM CELL; IN VITRO STUDY; JUVENILE MYELOMONOCYTIC LEUKEMIA; LOXP SITE; MONOCYTE; MOUSE; MYELOID LEUKEMIA; MYELOID PROGENITOR CELL; MYELOPROLIFERATIVE NEOPLASM; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; SPLEEN CELL; TUMOR XENOGRAFT;

ANIMALS; CELL LINE, TUMOR; ERYTHROPOIESIS; GENES, RAS; HEMATOPOIESIS; HETEROGRAFTS; HUMANS; LEUKEMIA, MYELOID, ACUTE; LEUKEMIA, MYELOMONOCYTIC, JUVENILE; MAP KINASE SIGNALING SYSTEM; MICE; MICE, INBRED C57BL; MICE, KNOCKOUT; PHOSPHATIDYLINOSITOL 3-KINASES; SIGNAL TRANSDUCTION;

EID: 84897541015     PISSN: 00219738     EISSN: 15588238     Source Type: Journal    
DOI: 10.1172/JCI69927     Document Type: Article

References (53)

1. Polak R, Buitenhuis M. The PI3K/PKB signaling module as key regulator of hematopoiesis: implications for therapeutic strategies in leukemia. Blood. 2012;119(4):911-923.
2. Vanhaesebroeck B, Ali K, Bilancio A, Geering B, Foukas LC. Signalling by PI3K isoforms: insights from gene-targeted mice. Trends Biochem Sci. 2005;30(4):194-204. (Pubitemid 40463309)
3. Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007;129(7):1261-1274. (Pubitemid 46962095)
4. Samuels Y, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004;304(5670):554. (Pubitemid 38541907)
5. Jia S, Roberts TM, Zhao JJ. Should individual PI3 kinase isoforms be targeted in cancer? Curr Opin Cell Biol. 2009;21(2):199-208.
6. Brana I, Siu LL. Clinical development of phosphatidylinositol 3-kinase inhibitors for cancer treatment. BMC Med. 2012;10(1):161.
7. Buitenhuis M, et al. Protein kinase B (c-akt) regulates hematopoietic lineage choice decisions during myelopoiesis. Blood. 2008;111(1):112-121.
8. Haneline LS, et al. Genetic reduction of class IA PI-3 kinase activity alters fetal hematopoiesis and competitive repopulating ability of hematopoietic stem cells in vivo. Blood. 2006;107(4):1375-1382. (Pubitemid 43242371)
9. Juntilla MM, Patil VD, Calamito M, Joshi RP, Birnbaum MJ, Koretzky GA. AKT1 and AKT2 maintain hematopoietic stem cell function by regulating reactive oxygen species. Blood. 2010;115(20):4030-4038.
10. Yilmaz OH, et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature. 2006;441(7092):475-482. (Pubitemid 44050144)
11. Zhang J, et al. PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention. Nature. 2006;441(7092):518-522. (Pubitemid 44050154)
12. Tothova Z, et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell. 2007;128(2):325-339. (Pubitemid 46137992)
13. Kharas MG, et al. Constitutively active AKT depletes hematopoietic stem cells induces leukemia in mice. Blood. 2010;115(7):1406-1415.
14. Chen C, et al. TSC-mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species. J Exp Med. 2008;205(10):2397-2408.
15. Bi L, Okabe I, Bernard DJ, Wynshaw-Boris A, Nussbaum RL. Proliferative defect and embryonic lethality in mice homozygous for a deletion in the p110aα subunit of phosphoinositide 3-kinase. J Biol Chem. 1999;274(16):10963-10968.
16. Jou ST, et al. Essential, nonredundant role for the phosphoinositide 3-kinase p110δ in signaling by the B-cell receptor complex. Mol Cell Biol. 2002;22(24):8580-8591.
17. Bi L, Okabe I, Bernard DJ, Nussbaum RL. Early embryonic lethality in mice deficient in the p110β catalytic subunit of PI 3-kinase. Mamm Genome. 2002;13(3):169-172. (Pubitemid 34185317)
18. Zhao JJ, et al. The p110α isoform of PI3K is essential for proper growth factor signaling and oncogenic transformation. Proc Natl Acad Sci U S A. 2006;103(44):16296-16300. (Pubitemid 44715190)
19. Utermark T, et al. The p110α and p110β isoforms of PI3K play divergent roles in mammary gland development and tumorigenesis. Genes Dev. 2012;26(14):1573-1586.
20. Gupta S, et al. Binding of ras to phosphoinositide 3-kinase p110α is required for ras-driven tumorigenesis in mice. Cell. 2007;129(5):957-968. (Pubitemid 46802703)
21. Fritsch C, et al. Abstract 3748: NVP-BYL719, a novel PI3Kalpha selective inhibitor with all the characteristics required for clinical development as an anticancer agent. Poster presented at: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; March 31, 2012-April 4, 2012; Chicago, Illinois, USA. Abstract nr 3748.
22. Juric D, et al. Abstract CT-01: BYL719, a next generation PI3K alpha specific inhibitor: Preliminary safety, PK, and efficacy results from the first-inhuman study. Paper presented at: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; March 31, 2012-April 4, 2012; Chicago, Illinois, USA. Abstract nr CT-01.
23. Xing Y, Gerhard B, Hogge DE. Selective small molecule inhibitors of p110α and δ isoforms of phosphoinosityl-3-kinase are cytotoxic to human acute myeloid leukemia progenitors. Exp Hematol. 2012;40(11):922-933.
24. Patel JP, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366(12):1079-1089.
25. Ward AF, Braun BS, Shannon KM. Targeting oncogenic Ras signaling in hematologic malignancies. Blood. 2012;120(17):3397-3406.
26. Castellano E, Downward J. Role of RAS in the regulation of PI 3-kinase. Curr Top Microbiol Immunol. 2010;346:143-169.
27. Staser K, et al. Normal hematopoiesis neurofibro-min- deficient myeloproliferative disease require Erk. J Clin Invest. 2013;123(1):329-334.
28. Chang T, et al. Sustained MEK inhibition abrogates myeloproliferative disease in Nf1 mutant mice. J Clin Invest. 2013;123(1):335-339.
29. Lyubynska N, et al. A MEK inhibitor abrogates myeloproliferative disease in Kras mutant mice. Sci Transl Med. 2011;3(76):76ra27.
30. Sos ML, et al. Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer. Proc Natl Acad Sci U S A. 2009;106(43):18351-18356.
31. Engelman JA, et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med. 2008; 14(12):1351-1356.
32. Furet P, et al. Discovery of NVP-BYL719 a potent and selective phosphatidylinositol-3 kinase ± inhibitor selected for clinical evaluation. Bioorg Med Chem Lett. 2013;23(13):3741-3748.
33. Ascierto PA, et al. MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study. Lancet Oncol. 2013;14(3):249-256.
34. Kuhn R, Schwenk F, Aguet M, Rajewsky K. Inducible gene targeting in mice. Science. 1995;269(5229):1427-1429.
35. Socolovsky M, Nam H, Fleming MD, Haase VH, Brugnara C, Lodish HF. Ineffective erythropoiesis in Stat5a(-/-)5b(-/-) mice due to decreased survival of early erythroblasts. Blood. 2001;98(12):3261-3273.
36. Growney JD, et al. Loss of Runx1 perturbs adult hematopoiesis and is associated with a myeloproliferative phenotype. Blood. 2005;106(2):494-504. (Pubitemid 40981243)
37. Cheng T, et al. Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science. 2000;287(5459):1804-1808.
38. Braun BS, et al. Somatic activation of oncogenic Kras in hematopoietic cells initiates a rapidly fatal myeloproliferative disorder. Proc Natl Acad Sci U S A. 2004;101(2):597-602. (Pubitemid 38084682)
39. Chan IT, et al. Conditional expression of oncogenic K-ras from its endogenous promoter induces a myeloproliferative disease. J Clin Invest. 2004;113(4):528-538. (Pubitemid 38542502)
40. Koul D, et al. Antitumor activity of NVP-BKM120 - a selective pan class I PI3 kinase inhibitor showed differential forms of cell death based on p53 status of glioma cells. Clin Cancer Res. 2012;18(1):184-195.
41. Herman SE, et al. Phosphatidylinositol 3-kinase-delta inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood. 2010;116(12):2078-2088.
42. Chaussade C, et al. Evidence for functional redundancy of class IA PI3K isoforms in insulin signalling. Biochem J. 2007;404(3):449-458. (Pubitemid 46953919)
43. Bruce I, et al. Development of isoform selective PI3-kinase inhibitors as pharmacological tools for elucidating the PI3K pathway. Bioorg Med Chem Lett. 2012;22(17):5445-5450.
44. Morgan MA, Dolp O, Reuter CW. Cell-cycle-dependent activation of mitogen-activated protein kinase kinase (MEK-1/2) in myeloid leukemia cell lines and induction of growth inhibition and apoptosis by inhibitors of RAS signaling. Blood. 2001;97(6):1823-1834. (Pubitemid 32217252)
45. Scholl C, et al. Synthetic lethal interaction between oncogenic KRAS dependency and STK33 suppression in human cancer cells. Cell. 2009;137(5):821-834.
46. Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer. 2009;9(8):550-562.
47. Ghaffari S, et al. AKT induces erythroid-cell maturation of JAK2-deficient fetal liver progenitor cells and is required for Epo regulation of erythroid-cell differentiation. Blood. 2006;107(5):1888-1891. (Pubitemid 43289367)
48. Bouscary D, et al. Critical role for PI 3-kinase in the control of erythropoietin-induced erythroid progenitor proliferation. Blood. 2003;101(9):3436-3443. (Pubitemid 36857926)
49. Zhao W, Kitidis C, Fleming MD, Lodish HF, Ghaffari S. Erythropoietin stimulates phosphorylation and activation of GATA-1 via the PI3-kinase/AKT signaling pathway. Blood. 2006;107(3):907-915. (Pubitemid 43158401)
50. Wu H, Liu X, Jaenisch R, Lodish HF. Generation of committed erythroid BFU-E and CFU-E progenitors does not require erythropoietin or the erythropoietin receptor. Cell. 1995;83(1):59-67.
51. Rahmani M, et al. The BH3-only protein Bim plays a critical role in leukemia cell death triggered by concomitant inhibition of the PI3K/Akt and MEK/ERK1/2 pathways. Blood. 2009;114(20):4507-4516.
52. Shimizu T, et al. The clinical effect of the dual-targeting strategy involving PI3K/AKT/mTOR and RAS/MEK/ERK pathways in patients with advanced cancer. Clin Cancer Res. 2012;18(8):2316-2325.
53. LoRusso P, et al. A first-in-human phase Ib study to evaluate the MEK inhibitor GDC-0973, combined with the pan-PI3K inhibitor GDC-941, in patients with advanced solid tumors. J Clin Oncol (Meeting Abstracts). 2012;30(15 Suppl.):2566.