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10.02.2018 | Original Article

Leukemia-propagating cells demonstrate distinctive gene expression profiles compared with other cell fractions from patients with de novo Philadelphia chromosome-positive ALL

verfasst von: Hong-Yan Zhao, Yang Song, Xie-Na Cao, Ya-Zhen Qin, Yue-Yun Lai, Hao Jiang, Qian Jiang, Xiao-Jun Huang, Yuan Kong

Erschienen in: Annals of Hematology | Ausgabe 5/2018

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Abstract

Relapse remains one of the major obstacles in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph⁺ALL) even after allogeneic hematopoietic stem cell transplantation. The persistence of leukemia-propagating cells (LPCs) may lead to the recurrence of Ph⁺ALL. Using a xenograft assay, LPCs enrichment in the CD34⁺CD38⁻CD58⁻ fraction in Ph⁺ALL was recently identified. A further cohort study indicated that the LPCs phenotype at diagnosis was an independent risk factor for relapse of Ph⁺ALL. However, little is known about the potential molecular mechanism of LPCs-mediated relapse. Therefore, the gene expression profiles of the sorted LPCs and other cell fractions from patients with de novo Ph⁺ALL were investigated using RNA sequencing (RNA-Seq). Most of the differentially expressed genes between the LPCs and other cell fractions were related to the regulation of the cell cycle and metabolism, as identified by the gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Consistent with the RNA-Seq results, the mRNA levels of cell cycle-related genes, such as cyclin-dependent kinase 4, were significantly lower in the LPCs fraction than in other cell fractions. Moreover, the proportion of quiescent cells in LPCs was significantly higher than in other cell fractions. In summary, distinctive gene expression profiles and clusters, which were mostly related to the regulation of the cell cycle and metabolism, were demonstrated between LPCs and other cell fractions from patients with de novo Ph⁺ALL. Therefore, it would be beneficial to develop novel LPCs-based therapeutic strategies for Ph⁺ALL patients.

Ottmann OG (2012) Management of Philadelphia chromosome-positive acute lymphoblastic leukemia. Leuk Suppl 1(Suppl 2):S7–S9. https://doi.org/10.1038/leusup.2012.7 CrossRefPubMedCentralPubMed

Ottmann OG, Pfeifer H (2009) First-line treatment of Philadelphia chromosome-positive acute lymphoblastic leukaemia in adults. Curr Opin Oncol 21(Suppl 1):S43–S46. https://doi.org/10.1097/01.cco.0000357476.43164.6b CrossRefPubMed

Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH (2014) UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood 123(6):843–850. https://doi.org/10.1182/blood-2013-09-529008 CrossRefPubMedCentralPubMed

Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, Minden M, Paterson B, Caligiuri MA, Dick JE (1994) A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367(6464):645–648. https://doi.org/10.1038/367645a0 CrossRefPubMed

Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 100(7):3983–3988. https://doi.org/10.1073/pnas.0530291100 CrossRefPubMedCentralPubMed

Burns JS, Abdallah BM, Guldberg P, Rygaard J, Schroder HD, Kassem M (2005) Tumorigenic heterogeneity in cancer stem cells evolved from long-term cultures of telomerase-immortalized human mesenchymal stem cells. Cancer Res 65(8):3126–3135. https://doi.org/10.1158/0008-5472.CAN-04-2218 CrossRefPubMed

Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ (2005) Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res 65(23):10946–10951. https://doi.org/10.1158/0008-5472.CAN-05-2018 CrossRefPubMed

Kim CF, Jackson EL, Woolfenden AE, Lawrence S, Babar I, Vogel S, Crowley D, Bronson RT, Jacks T (2005) Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 121(6):823–835. https://doi.org/10.1016/j.cell.2005.03.032 CrossRefPubMed

O'Brien CA, Pollett A, Gallinger S, Dick JE (2007) A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445(7123):106–110. https://doi.org/10.1038/nature05372 CrossRefPubMed

10.

Piccirillo SG, Reynolds BA, Zanetti N, Lamorte G, Binda E, Broggi G, Brem H, Olivi A, Dimeco F, Vescovi AL (2006) Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature 444(7120):761–765. https://doi.org/10.1038/nature05349 CrossRefPubMed

11.

Szotek PP, Pieretti-Vanmarcke R, Masiakos PT, Dinulescu DM, Connolly D, Foster R, Dombkowski D, Preffer F, Maclaughlin DT, Donahoe PK (2006) Ovarian cancer side population defines cells with stem cell-like characteristics and Mullerian inhibiting substance responsiveness. Proc Natl Acad Sci U S A 103(30):11154–11159. https://doi.org/10.1073/pnas.0603672103 CrossRefPubMedCentralPubMed

12.

Abdel-Wahab O, Mullally A, Hedvat C, Garcia-Manero G, Patel J, Wadleigh M, Malinge S, Yao J, Kilpivaara O, Bhat R, Huberman K, Thomas S, Dolgalev I, Heguy A, Paietta E, Le Beau MM, Beran M, Tallman MS, Ebert BL, Kantarjian HM, Stone RM, Gilliland DG, Crispino JD, Levine RL (2009) Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood 114(1):144–147. https://doi.org/10.1182/blood-2009-03-210039 CrossRefPubMedCentralPubMed

13.

Ernst T, Chase AJ, Score J, Hidalgo-Curtis CE, Bryant C, Jones AV, Waghorn K, Zoi K, Ross FM, Reiter A, Hochhaus A, Drexler HG, Duncombe A, Cervantes F, Oscier D, Boultwood J, Grand FH, Cross NC (2010) Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat Genet 42(8):722–726. https://doi.org/10.1038/ng.621 CrossRefPubMed

14.

Greif PA, Eck SH, Konstandin NP, Benet-Pages A, Ksienzyk B, Dufour A, Vetter AT, Popp HD, Lorenz-Depiereux B, Meitinger T, Bohlander SK, Strom TM (2011) Identification of recurring tumor-specific somatic mutations in acute myeloid leukemia by transcriptome sequencing. Leukemia 25(5):821–827. https://doi.org/10.1038/leu.2011.19 CrossRefPubMed

15.

Ley TJ, Ding L, Walter MJ, McLellan MD, Lamprecht T, Larson DE, Kandoth C, Payton JE, Baty J, Welch J, Harris CC, Lichti CF, Townsend RR, Fulton RS, Dooling DJ, Koboldt DC, Schmidt H, Zhang Q, Osborne JR, Lin L, O'Laughlin M, McMichael JF, Delehaunty KD, McGrath SD, Fulton LA, Magrini VJ, Vickery TL, Hundal J, Cook LL, Conyers JJ, Swift GW, Reed JP, Alldredge PA, Wylie T, Walker J, Kalicki J, Watson MA, Heath S, Shannon WD, Varghese N, Nagarajan R, Westervelt P, Tomasson MH, Link DC, Graubert TA, DiPersio JF, Mardis ER, Wilson RK (2010) DNMT3A mutations in acute myeloid leukemia. N Engl J Med 363(25):2424–2433. https://doi.org/10.1056/NEJMoa1005143 CrossRefPubMedCentralPubMed

16.

Ley TJ, Mardis ER, Ding L, Fulton B, McLellan MD, Chen K, Dooling D, Dunford-Shore BH, McGrath S, Hickenbotham M, Cook L, Abbott R, Larson DE, Koboldt DC, Pohl C, Smith S, Hawkins A, Abbott S, Locke D, Hillier LW, Miner T, Fulton L, Magrini V, Wylie T, Glasscock J, Conyers J, Sander N, Shi X, Osborne JR, Minx P, Gordon D, Chinwalla A, Zhao Y, Ries RE, Payton JE, Westervelt P, Tomasson MH, Watson M, Baty J, Ivanovich J, Heath S, Shannon WD, Nagarajan R, Walter MJ, Link DC, Graubert TA, DiPersio JF, Wilson RK (2008) DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome. Nature 456(7218):66–72. https://doi.org/10.1038/nature07485 CrossRefPubMedCentralPubMed

17.

Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K, Koboldt DC, Fulton RS, Delehaunty KD, McGrath SD, Fulton LA, Locke DP, Magrini VJ, Abbott RM, Vickery TL, Reed JS, Robinson JS, Wylie T, Smith SM, Carmichael L, Eldred JM, Harris CC, Walker J, Peck JB, Du F, Dukes AF, Sanderson GE, Brummett AM, Clark E, McMichael JF, Meyer RJ, Schindler JK, Pohl CS, Wallis JW, Shi X, Lin L, Schmidt H, Tang Y, Haipek C, Wiechert ME, Ivy JV, Kalicki J, Elliott G, Ries RE, Payton JE, Westervelt P, Tomasson MH, Watson MA, Baty J, Heath S, Shannon WD, Nagarajan R, Link DC, Walter MJ, Graubert TA, DiPersio JF, Wilson RK, Ley TJ (2009) Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med 361(11):1058–1066. https://doi.org/10.1056/NEJMoa0903840 CrossRefPubMedCentralPubMed

18.

Nikoloski G, Langemeijer SM, Kuiper RP, Knops R, Massop M, Tonnissen ER, van der Heijden A, Scheele TN, Vandenberghe P, de Witte T, van der Reijden BA, Jansen JH (2010) Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes. Nat Genet 42(8):665–667. https://doi.org/10.1038/ng.620 CrossRefPubMed

19.

Yan XJ, Xu J, Gu ZH, Pan CM, Lu G, Shen Y, Shi JY, Zhu YM, Tang L, Zhang XW, Liang WX, Mi JQ, Song HD, Li KQ, Chen Z, Chen SJ (2011) Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia. Nat Genet 43(4):309–315. https://doi.org/10.1038/ng.788 CrossRefPubMed

20.

Eppert K, Takenaka K, Lechman ER, Waldron L, Nilsson B, van Galen P, Metzeler KH, Poeppl A, Ling V, Beyene J, Canty AJ, Danska JS, Bohlander SK, Buske C, Minden MD, Golub TR, Jurisica I, Ebert BL, Dick JE (2011) Stem cell gene expression programs influence clinical outcome in human leukemia. Nat Med 17(9):1086–1093. https://doi.org/10.1038/nm.2415 CrossRefPubMed

21.

Cobaleda C, Gutierrez-Cianca N, Perez-Losada J, Flores T, Garcia-Sanz R, Gonzalez M, Sanchez-Garcia I (2000) A primitive hematopoietic cell is the target for the leukemic transformation in human philadelphia-positive acute lymphoblastic leukemia. Blood 95(3):1007–1013PubMed

22.

Kong Y, Chang YJ, Liu YR, Wang YZ, Jiang Q, Jiang H, Qin YZ, Hu Y, Lai YY, Duan CW, Hong DL, Huang XJ (2014) CD34(+)CD38(-)CD58(-) cells are leukemia-propagating cells in Philadelphia chromosome-positive acute lymphoblastic leukemia. Leukemia 28(12):2398–2401. https://doi.org/10.1038/leu.2014.228 CrossRefPubMed

23.

Kong Y, Xu LP, Liu YR, Qin YZ, Sun YQ, Wang Y, Jiang H, Jiang Q, Chen H, Chang YJ, Huang XJ (2015) Presence of CD34(+)CD38(-)CD58(-) leukemia-propagating cells at diagnosis identifies patients at high risk of relapse with Ph chromosome-positive ALL after allo-hematopoietic SCT. Bone Marrow Transplant 50(3):348–353. https://doi.org/10.1038/bmt.2014.274 CrossRefPubMed

24.

Kerpedjiev P, Frellsen J, Lindgreen S, Krogh A (2014) Adaptable probabilistic mapping of short reads using position specific scoring matrices. BMC Bioinformatics 15(1):100. https://doi.org/10.1186/1471-2105-15-100 CrossRefPubMedCentralPubMed

25.

Kim D, Salzberg SL (2011) TopHat-fusion: an algorithm for discovery of novel fusion transcripts. Genome Biol 12(8):R72. https://doi.org/10.1186/gb-2011-12-8-r72 CrossRefPubMedCentralPubMed

26.

Anders S, Pyl PT, Huber W (2015) HTSeq—a python framework to work with high-throughput sequencing data. Bioinformatics 31(2):166–169. https://doi.org/10.1093/bioinformatics/btu638 CrossRefPubMed

27.

Mortazavi A, Williams BA, McCue K, Schaeffer L, Wold B (2008) Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat Methods 5(7):621–628. https://doi.org/10.1038/nmeth.1226 CrossRefPubMed

28.

Benjamini Y, Drai D, Elmer G, Kafkafi N, Golani I (2001) Controlling the false discovery rate in behavior genetics research. Behav Brain Res 125(1–2):279–284CrossRefPubMed

29.

Chen H, Boutros PC (2011) VennDiagram: a package for the generation of highly-customizable Venn and Euler diagrams in R. BMC Bioinformatics 12(1):35. https://doi.org/10.1186/1471-2105-12-35 CrossRefPubMedCentralPubMed

30.

Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, Harris MA, Hill DP, Issel-Tarver L, Kasarskis A, Lewis S, Matese JC, Richardson JE, Ringwald M, Rubin GM, Sherlock G (2000) Gene ontology: tool for the unification of biology. The gene ontology consortium. Nat Genet 25(1):25–29. https://doi.org/10.1038/75556 CrossRefPubMedCentralPubMed

31.

Kanehisa M, Araki M, Goto S, Hattori M, Hirakawa M, Itoh M, Katayama T, Kawashima S, Okuda S, Tokimatsu T, Yamanishi Y (2008) KEGG for linking genomes to life and the environment. Nucleic Acids Res 36(Database issue):D480–D484. https://doi.org/10.1093/nar/gkm882 PubMed

32.

Xie C, Mao X, Huang J, Ding Y, Wu J, Dong S, Kong L, Gao G, Li CY, Wei L (2011) KOBAS 2.0: a web server for annotation and identification of enriched pathways and diseases. Nucleic Acids Res 39(Web Server issue):W316–W322. https://doi.org/10.1093/nar/gkr483 CrossRefPubMedCentralPubMed

33.

Cheshier SH, Morrison SJ, Liao X, Weissman IL (1999) In vivo proliferation and cell cycle kinetics of long-term self-renewing hematopoietic stem cells. Proc Natl Acad Sci U S A 96(6):3120–3125. https://doi.org/10.1073/pnas.96.6.3120 CrossRefPubMedCentralPubMed

34.

Tesio M, Trumpp A (2011) Breaking the cell cycle of HSCs by p57 and friends. Cell Stem Cell 9(3):187–192. https://doi.org/10.1016/j.stem.2011.08.005 CrossRefPubMed

35.

Wilson A, Laurenti E, Oser G, van der Wath RC, Blanco-Bose W, Jaworski M, Offner S, Dunant CF, Eshkind L, Bockamp E, Lio P, Macdonald HR, Trumpp A (2008) Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell 135(6):1118–1129. https://doi.org/10.1016/j.cell.2008.10.048 CrossRefPubMed

36.

Passegue E, Wagers AJ, Giuriato S, Anderson WC, Weissman IL (2005) Global analysis of proliferation and cell cycle gene expression in the regulation of hematopoietic stem and progenitor cell fates. J Exp Med 202(11):1599–1611. https://doi.org/10.1084/jem.20050967 CrossRefPubMedCentralPubMed

37.

Lagadinou ED, Sach A, Callahan K, Rossi RM, Neering SJ, Minhajuddin M, Ashton JM, Pei S, Grose V, O'Dwyer KM, Liesveld JL, Brookes PS, Becker MW, Jordan CT (2013) BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell 12(3):329–341. https://doi.org/10.1016/j.stem.2012.12.013 CrossRefPubMedCentralPubMed

38.

Ebinger S, Ozdemir EZ, Ziegenhain C, Tiedt S, Castro Alves C, Grunert M, Dworzak M, Lutz C, Turati VA, Enver T, Horny HP, Sotlar K, Parekh S, Spiekermann K, Hiddemann W, Schepers A, Polzer B, Kirsch S, Hoffmann M, Knapp B, Hasenauer J, Pfeifer H, Panzer-Grumayer R, Enard W, Gires O, Jeremias I (2016) Characterization of rare, dormant, and therapy-resistant cells in acute lymphoblastic leukemia. Cancer Cell 30(6):849–862. https://doi.org/10.1016/j.ccell.2016.11.002 CrossRefPubMedCentralPubMed

39.

Aleem E, Arceci RJ (2015) Targeting cell cycle regulators in hematologic malignancies. Front Cell Dev Biol 3:16. https://doi.org/10.3389/fcell.2015.00016 CrossRefPubMedCentralPubMed

40.

Malumbres M, Sotillo R, Santamaria D, Galan J, Cerezo A, Ortega S, Dubus P, Barbacid M (2004) Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6. Cell 118(4):493–504. https://doi.org/10.1016/j.cell.2004.08.002 CrossRefPubMed

41.

Laurenti E, Frelin C, Xie S, Ferrari R, Dunant CF, Zandi S, Neumann A, Plumb I, Doulatov S, Chen J, April C, Fan JB, Iscove N, Dick JE (2015) CDK6 levels regulate quiescence exit in human hematopoietic stem cells. Cell Stem Cell 16(3):302–313. https://doi.org/10.1016/j.stem.2015.01.017 CrossRefPubMedCentralPubMed

42.

Nemoto A, Saida S, Kato I, Kikuchi J, Furukawa Y, Maeda Y, Akahane K, Honna-Oshiro H, Goi K, Kagami K, Kimura S, Sato Y, Okabe S, Niwa A, Watanabe K, Nakahata T, Heike T, Sugita K, Inukai T (2016) Specific antileukemic activity of PD0332991, a CDK4/6 inhibitor, against Philadelphia chromosome-positive lymphoid leukemia. Mol Cancer Ther 15(1):94–105. https://doi.org/10.1158/1535-7163.MCT-14-1065 CrossRefPubMed

43.

Pei S, Minhajuddin M, Callahan KP, Balys M, Ashton JM, Neering SJ, Lagadinou ED, Corbett C, Ye H, Liesveld JL, O'Dwyer KM, Li Z, Shi L, Greninger P, Settleman J, Benes C, Hagen FK, Munger J, Crooks PA, Becker MW, Jordan CT (2013) Targeting aberrant glutathione metabolism to eradicate human acute myelogenous leukemia cells. J Biol Chem 288(47):33542–33558. https://doi.org/10.1074/jbc.M113.511170 CrossRefPubMedCentralPubMed

44.

Forman HJ, Zhang H, Rinna A (2009) Glutathione: overview of its protective roles, measurement, and biosynthesis. Mol Asp Med 30(1–2):1–12. https://doi.org/10.1016/j.mam.2008.08.006 CrossRef

45.

Hole PS, Pearn L, Tonks AJ, James PE, Burnett AK, Darley RL, Tonks A (2010) Ras-induced reactive oxygen species promote growth factor-independent proliferation in human CD34+ hematopoietic progenitor cells. Blood 115(6):1238–1246. https://doi.org/10.1182/blood-2009-06-222869 CrossRefPubMed

Titel: Leukemia-propagating cells demonstrate distinctive gene expression profiles compared with other cell fractions from patients with de novo Philadelphia chromosome-positive ALL
verfasst von: Hong-Yan Zhao
Yang Song
Xie-Na Cao
Ya-Zhen Qin
Yue-Yun Lai
Hao Jiang
Qian Jiang
Xiao-Jun Huang
Yuan Kong
Publikationsdatum: 10.02.2018
Verlag: Springer Berlin Heidelberg
Erschienen in: Annals of Hematology / Ausgabe 5/2018
Print ISSN: 0939-5555
Elektronische ISSN: 1432-0584
DOI: https://doi.org/10.1007/s00277-018-3253-5

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Leukemia-propagating cells demonstrate distinctive gene expression profiles compared with other cell fractions from patients with de novo Philadelphia chromosome-positive ALL

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