Blockage of autophagic flux is associated with lymphocytosis and higher percentage of tumoral cells in chronic lymphocytic leukemia of B cells

  • J.-R. Romero-Macías
  • R. Pascual-Serra
  • O. Roche
  • F. Ruiz-Marcos
  • A. Serrano-Martínez
  • P. González-Aguado
  • B. Belandia
  • M.-J. Ruiz-Hidalgo
  • R. Sánchez-PrietoEmail author
Brief Research Article



Autophagy has lately emerged as an important biological process with implications in several hematological pathologies. Recently, a growing body of evidence supports a putative role of autophagy in chronic lymphocytic leukemia; however, no definitive clue has been established so far. To elucidate this issue, we have developed a pilot study to measure autophagic flux in peripheral blood mononuclear cells from chronic lymphocytic leukemia patients, and explored its correlation with classical clinical/analytical parameters.


Thirty-three chronic lymphocytic leukemia patients participated in the study. Autophagic flux in peripheral blood mononuclear cells was determined by western blot measuring the levels of the proteins p62 and lipidated LC3. Moreover, p62 mRNA levels were analyzed by RT-qPCR.


Lymphocytosis and the percentage of tumoral lymphocytes in chronic lymphocytic leukemia patients statistically correlate with a blocked autophagic flux.


Alterations in autophagic flux could play an important role in the physiopathology of chronic lymphocytic leukemia.


Autophagy Chronic lymphocytic leukemia p62 LC3 Autophagic flux 



Chronic lymphocytic leukemia of B cells


Western blot


Peripheral blood mononuclear cells





We appreciate the helpful collaboration of Dr. Manuel Gerónimo-Pardo and Dr. José Javier García Ramírez. This work was supported by Grants from Fundación Leticia Castillejo Castillo, Ministerio de Economía y Competitividad (SAF2012-30862, SAF2015-64215R to RSP and MJRH) and Sociedad Castellano Manchega de Hematología y Hemoterapia (to JRRM). OR has a contract for access to the Spanish System of Science, Technology and Innovation (SECTI) funded by the University of Castilla-La Mancha (UCLM). RPS has a predoctoral contract for the training of research staff funded by the University of Castilla-La Mancha (UCLM) (2014/10340). RSP and MJRH Research Institutes, and the work carried out in their laboratories received support from the European Community through the Regional Development Funding Program (FEDER).

Compliance with ethical standards

Conflict of interest

The authors have no competing interests.

Informed consent

Samples from patients and healthy donors were used after obtaining appropriate informed consent.

Ethical statement

This study was approved by the Ethical and Research Committee of the “Complejo Hospitalario Universitario de Albacete”.


  1. 1.
    Rabinowitz JD, White E. Autophagy and metabolism. Science. 2010;330:1344–8.CrossRefGoogle Scholar
  2. 2.
    White E. Deconvoluting the context-dependent role for autophagy in cancer. Nat Rev Cancer. 2012;12:401–10.CrossRefGoogle Scholar
  3. 3.
    Coll-Mulet L, Gil J. Genetic alterations in chronic lymphocytic leukaemia. Clin Transl Oncol. 2009;11:194–8.CrossRefGoogle Scholar
  4. 4.
    Soderguist RS, Eastman A. BCL2 inhibitors as anticancer drugs: a plethora of misleading BH3 mimetics. Mol Cancer Ther. 2016;15(9):2011–7.CrossRefGoogle Scholar
  5. 5.
    Jain MV, et al. Interconnections between apoptotic, autophagic and necrotic pathways: implications for cancer therapy development. J Cell Mol Med. 2013;17:12–29.CrossRefGoogle Scholar
  6. 6.
    Watanabe K, Tsubata T. Autophagy connects antigen receptor signaling to costimulatory signaling in B lymphocytes. Autophagy. 2009;5:108–10.CrossRefGoogle Scholar
  7. 7.
    Bologna C, et al. SLAMF1 regulation of chemotaxis and autophagy determines CLL patient response. J Clin Invest. 2016;126:181–94.CrossRefGoogle Scholar
  8. 8.
    Kong YL, et al. Expression of autophagy related genes in chronic lymphocytic leukemia is associated with disease course. Leuk Res. 2018;66:8–14.CrossRefGoogle Scholar
  9. 9.
    Liu D, et al. Autophagy regulates the survival of cells with chromosomal instability. Oncotarget. 2016;7:63913–23.Google Scholar
  10. 10.
    Stellrecht CM, et al. Chlorinated adenosine analogue induces AMPK and autophagy in chronic lymphocytic leukaemia cells during therapy. Br J Haematol. 2017;179:266–71.CrossRefGoogle Scholar
  11. 11.
    Hallek M, et al. Guidelines for diagnosis, indications for treatment, response assessment and supportive management of chronic lymphocytic leukemia. Blood. 2018. Scholar
  12. 12.
    Qu X, et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest. 2003;112:1809–20.CrossRefGoogle Scholar
  13. 13.
    Blunt MD, et al. The PI3K/mTOR inhibitor PF-04691502 induces apoptosis and inhibits micro environmental signaling in CLL and the Eµ-TCL1 mouse model. Blood. 2015;125:4032–41.CrossRefGoogle Scholar
  14. 14.
    Albanell J, et al. mTOR signalling in human cancer. Clin Transl Oncol. 2007;9:484–93.CrossRefGoogle Scholar

Copyright information

© Federación de Sociedades Españolas de Oncología (FESEO) 2019

Authors and Affiliations

  • J.-R. Romero-Macías
    • 1
    • 2
  • R. Pascual-Serra
    • 2
  • O. Roche
    • 2
    • 3
    • 4
  • F. Ruiz-Marcos
    • 1
  • A. Serrano-Martínez
    • 1
  • P. González-Aguado
    • 1
  • B. Belandia
    • 5
    • 6
  • M.-J. Ruiz-Hidalgo
    • 2
    • 3
    • 7
  • R. Sánchez-Prieto
    • 4
    • 5
    • 6
    Email author
  1. 1.Servicio de HematologíaComplejo Hospitalario Universitario de AlbaceteAlbaceteSpain
  2. 2.Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Centro Regional de Investigaciones BiomédicasUniversidad de Castilla-La ManchaAlbaceteSpain
  3. 3.Unidad Asociada de Biomedicina CSIC-UCLMAlbaceteSpain
  4. 4.Departamento de Ciencias Médicas, Facultad de MedicinaUniversidad de Castilla-La ManchaAlbaceteSpain
  5. 5.Lab. 1.5.2, Departamento de Biología del CáncerInstituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM)MadridSpain
  6. 6.Unidad Asociada de Biomedicina CSIC-UCLMMadridSpain
  7. 7.Área de Bioquímica y Biología Molecular, Facultad de MedicinaUniversidad de Castilla-La ManchaAlbaceteSpain

Personalised recommendations