Top

Journal of Hematology & Oncology

Published in:

Open Access 01-12-2012 | Rapid communication

The significance of low PU.1 expression in patients with acute promyelocytic leukemia

Authors: Xuehua Zhu, Hui Zhang, Maoxiang Qian, Xujie Zhao, Wentao Yang, Ping Wang, Ji Zhang, Kankan Wang

Published in: Journal of Hematology & Oncology | Issue 1/2012

Abstract

Background

Although the importance of the hematopoietic transcription factor PU.1 in acute myeloid leukemia (AML) has been demonstrated, the expression of PU.1 in acute promyelocytic leukemia (APL) patient samples awaits further investigation. The current study used APL patient samples to assess the expression pattern of PU.1 in the initiation and progression of APL.

Findings

We used real-time RT-PCR to compare PU.1 expression between de novo APL patient samples and normal blood specimens, and the results indicated that PU.1 expression was significantly lower in newly diagnosed APL patient samples as compared to normal hematopoietic cells. Further evidence showed a significant inverse correlation between the expression level of PML-RARα and that of PU.1. In addition, we analyzed the correlation between PML-RARα and PU.1 expression in a large population of AML patients retrieved from the expression profiles. The results showed that PU.1 expression was lower in patients with APL than other AML subtypes and there was also a trend towards increasing PU.1 expression from AML-M0 to AML-M5, with the exception of AML-M3 (APL). These observations suggested that PU.1 expression was reduced by PML-RARα in APL patients. Furthermore, we measured PU.1 expression in APL-initiating cells isolated from de novo APL patients by side population cell analysis and found that suppression of PU.1 expression occurred concurrently with PML-RARα expression, indicating the pivotal role of PU.1 in APL initiation.

Conclusion

Our findings provide evidence that low PU.1 expression in APL patients is required for disease initiation and progression.

Available only for authorised users

Wang ZY, Chen Z: Acute promyelocytic leukemia: from highly fatal to highly curable. Blood. 2008, 111: 2505-2515. 10.1182/blood-2007-07-102798.CrossRefPubMed

Wang ZG, Delva L, Gaboli M, Rivi R, Giorgio M, Cordon-Cardo C, Grosveld F, Pandolfi PP: Role of PML in cell growth and the retinoic acid pathway. Science. 1998, 279: 1547-1551. 10.1126/science.279.5356.1547.CrossRefPubMed

Kastner P, Chan S: Function of RARalpha during the maturation of neutrophils. Oncogene. 2001, 20: 7178-7185. 10.1038/sj.onc.1204757.CrossRefPubMed

Grisolano JL, Wesselschmidt RL, Pelicci PG, Ley TJ: Altered myeloid development and acute leukemia in transgenic mice expressing PML-RAR alpha under control of cathepsin G regulatory sequences. Blood. 1997, 89: 376-387.PubMed

Wang K, Wang P, Shi J, Zhu X, He M, Jia X, Yang X, Qiu F, Jin W, Qian M, Fang H, Mi J, Yang X, Xiao H, Minden M, Du Y, Chen Z, Zhang J: PML/RARalpha targets promoter regions containing PU.1 consensus and RARE half sites in acute promyelocytic leukemia. Cancer Cell. 2010, 17: 186-197. 10.1016/j.ccr.2009.12.045.CrossRefPubMed

Mueller BU, Pabst T, Fos J, Petkovic V, Fey MF, Asou N, Buergi U, Tenen DG: ATRA resolves the differentiation block in t(15;17) acute myeloid leukemia by restoring PU.1 expression. Blood. 2006, 107: 3330-3338. 10.1182/blood-2005-07-3068.PubMedCentralCrossRefPubMed

Goodell MA, Brose K, Paradis G, Conner AS, Mulligan RC: Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J Exp Med. 1996, 183: 1797-1806. 10.1084/jem.183.4.1797.CrossRefPubMed

Gutierrez NC, Lopez-Perez R, Hernandez JM, Isidro I, Gonzalez B, Delgado M, Ferminan E, Garcia JL, Vazquez L, Gonzalez M, San Miguel JF: Gene expression profile reveals deregulation of genes with relevant functions in the different subclasses of acute myeloid leukemia. Leukemia. 2005, 19: 402-409. 10.1038/sj.leu.2403625.CrossRefPubMed

Tomasson MH, Xiang Z, Walgren R, Zhao Y, Kasai Y, Miner T, Ries RE, Lubman O, Fremont DH, McLellan MD, Payton JE, Westervelt P, DiPersio JF, Link DC, Walter MJ, Graubert TA, Watson M, Baty J, Heath S, Shannon WD, Nagarajan R, Bloomfield CD, Mardis ER, Wilson RK, Ley TJ: Somatic mutations and germline sequence variants in the expressed tyrosine kinase genes of patients with de novo acute myeloid leukemia. Blood. 2008, 111: 4797-4808. 10.1182/blood-2007-09-113027.PubMedCentralCrossRefPubMed

10.

Valk PJ, Verhaak RG, Beijen MA, Erpelinck CA, van Doorn-Khosrovani Barjesteh van Waalwijk, Boer JM, Beverloo HB, Moorhouse MJ, van der Spek PJ, Lowenberg B, Delwel R: Prognostically useful gene-expression profiles in acute myeloid leukemia. N Engl J Med. 2004, 350: 1617-1628. 10.1056/NEJMoa040465.CrossRefPubMed

11.

Ross ME, Mahfouz R, Onciu M, Liu HC, Zhou X, Song G, Shurtleff SA, Pounds S, Cheng C, Ma J, Ribeiro RC, Rubnitz JE, Girtman K, Williams WK, Raimondi SC, Liang DC, Shih LY, Pui CH, Downing JR: Gene expression profiling of pediatric acute myelogenous leukemia. Blood. 2004, 104: 3679-3687. 10.1182/blood-2004-03-1154.CrossRefPubMed

12.

Dahl R, Simon MC: The importance of PU.1 concentration in hematopoietic lineage commitment and maturation. Blood Cells Mol Dis. 2003, 31: 229-233. 10.1016/S1079-9796(03)00152-9.CrossRefPubMed

13.

Sainty D, Liso V, Cantu-Rajnoldi A, Head D, Mozziconacci MJ, Arnoulet C, Benattar L, Fenu S, Mancini M, Duchayne E, Mahon FX, Gutierrez N, Birg F, Biondi A, Grimwade D, Lafage-Pochitaloff M, Hagemeijer A, Flandrin G: A new morphologic classification system for acute promyelocytic leukemia distinguishes cases with underlying PLZF/RARA gene rearrangements. Group Francais de Cytogenetique Hematologique, UK Cancer Cytogenetics Group and BIOMED 1 European Coomunity-Concerted Acion "Molecular Cytogenetic Diagnosis in Haematological Malignancies. Blood. 2000, 96: 1287-1296.PubMed

14.

Zheng X, Seshire A, Ruster B, Bug G, Beissert T, Puccetti E, Hoelzer D, Henschler R, Ruthardt M: Arsenic but not all-trans retinoic acid overcomes the aberrant stem cell capacity of PML/RARalpha-positive leukemic stem cells. Haematologica. 2007, 92: 323-331. 10.3324/haematol.10541.CrossRefPubMed

15.

Parmar K, Mauch P, Vergilio JA, Sackstein R, Down JD: Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia. Proc Natl Acad Sci U S A. 2007, 104: 5431-5436. 10.1073/pnas.0701152104.PubMedCentralCrossRefPubMed

16.

Nutt SL, Metcalf D, D'Amico A, Polli M, Wu L: Dynamic regulation of PU.1 expression in multipotent hematopoietic progenitors. J Exp Med. 2005, 201: 221-231. 10.1084/jem.20041535.PubMedCentralCrossRefPubMed

17.

Rosenbauer F, Wagner K, Kutok JL, Iwasaki H, Le Beau MM, Okuno Y, Akashi K, Fiering S, Tenen DG: Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1. Nat Genet. 2004, 36: 624-630. 10.1038/ng1361.CrossRefPubMed

18.

Metcalf D, Dakic A, Mifsud S, Di RL, Wu L, Nutt S: Inactivation of PU.1 in adult mice leads to the development of myeloid leukemia. Proc Natl Acad Sci U S A. 2006, 103: 1486-1491. 10.1073/pnas.0510616103.PubMedCentralCrossRefPubMed

19.

Vangala RK, Heiss-Neumann MS, Rangatia JS, Singh SM, Schoch C, Tenen DG, Hiddemann W, Behre G: The myeloid master regulator transcription factor PU.1 is inactivated by AML1-ETO in t(8;21) myeloid leukemia. Blood. 2003, 101: 270-277. 10.1182/blood-2002-04-1288.CrossRefPubMed

20.

Lo CF, Pisegna S, Diverio D: The AML1 gene: a transcription factor involved in the pathogenesis of myeloid and lymphoid leukemias. Haematologica. 1997, 82: 364-370.

21.

Pollock JL, Westervelt P, Walter MJ, Lane AA, Ley TJ: Mouse models of acute promyelocytic leukemia. Curr Opin Hematol. 2001, 8: 206-211. 10.1097/00062752-200107000-00005.CrossRefPubMed

22.

Chan IT, Kutok JL, Williams IR, Cohen S, Moore S, Shigematsu H, Ley TJ, Akashi K, Le Beau MM, Gilliland DG: Oncogenic K-ras cooperates with PML-RAR alpha to induce an acute promyelocytic leukemia-like disease. Blood. 2006, 108: 1708-1715. 10.1182/blood-2006-04-015040.PubMedCentralCrossRefPubMed

23.

Kelly LM, Kutok JL, Williams IR, Boulton CL, Amaral SM, Curley DP, Ley TJ, Gilliland DG: PML/RARalpha and FLT3-ITD induce an APL-like disease in a mouse model. Proc Natl Acad Sci U S A. 2002, 99: 8283-8288. 10.1073/pnas.122233699.PubMedCentralCrossRefPubMed

24.

Kogan SC, Brown DE, Shultz DB, Truong BT, Lallemand-Breitenbach V, Guillemin MC, Lagasse E, Weissman IL, Bishop JM: BCL-2 cooperates with promyelocytic leukemia retinoic acid receptor alpha chimeric protein (PMLRARalpha) to block neutrophil differentiation and initiate acute leukemia. J Exp Med. 2001, 193: 531-543. 10.1084/jem.193.4.531.PubMedCentralCrossRefPubMed

25.

Walter MJ, Park JS, Ries RE, Lau SK, McLellan M, Jaeger S, Wilson RK, Mardis ER, Ley TJ: Reduced PU.1 expression causes myeloid progenitor expansion and increased leukemia penetrance in mice expressing PML-RARalpha. Proc Natl Acad Sci U S A. 2005, 102: 12513-12518. 10.1073/pnas.0504247102.PubMedCentralCrossRefPubMed

Title: The significance of low PU.1 expression in patients with acute promyelocytic leukemia
Authors: Xuehua Zhu
Hui Zhang
Maoxiang Qian
Xujie Zhao
Wentao Yang
Ping Wang
Ji Zhang
Kankan Wang
Publication date: 01-12-2012
Publisher: BioMed Central
Published in: Journal of Hematology & Oncology / Issue 1/2012
Electronic ISSN: 1756-8722
DOI: https://doi.org/10.1186/1756-8722-5-22

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Findings

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2012

Alternative expression of TCRζ related genes in patients with chronic myeloid leukemia

Novel therapeutic agents for cutaneous T-Cell lymphoma

MicroRNAs and Toll-like Receptor/Interleukin-1 Receptor Signaling

Cytoreduction surgery reduces systemic myeloid suppressor cell populations and restores intratumoral immunotherapy effectiveness

Opposite regulation by PI3K/Akt and MAPK/ERK pathways of tissue factor expression, cell-associated procoagulant activity and invasiveness in MDA-MB-231 cells

Increased CDC20 expression is associated with pancreatic ductal adenocarcinoma differentiation and progression

Keynote webinar | Spotlight on antibody–drug conjugates in cancer