Research profile:

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disease which is driven by a chromosomal translocation leading to the expression of BCR-ABL, a fusion protein with constitutive tyrosine kinase activity and accounts for approximately 20% of leukaemias diagnosed in adults. CML starts with a chronic phase, but due to genomic instability and activation of additional protective mechanisms, it progresses to blast crisis, becoming aggressive and increasingly resistant to therapy. The molecular mechanisms responsible for the progression are largely elusive. A specific inhibitor of the BCR-ABL tyrosine kinase - imatinib has been effective in the treatment of the chronic phase. However, imatinib responses in chronic phase lead to the development of drug resistance in 25 – 30% of cases, whereas in blast crisis are short-lived and efficient only in 20 – 25% of patients. Despite advances in CML treatment with a newer generation of BCR-ABL inhibitors (BCR-ABL tyrosine kinase inhibitors – imatinib, dasatinib) , the blastic phase remains almost inevitably fatal. Two major mechanisms bring about progression of the disease and further selection of resistant cancer cells upon treatment – genomic instability and adaptation to the changed microenvironment and stress conditions due to activation of survival mechanism. There is a need to elucidate adaptative, prosurvival pathways activated in chronic myeloid leukemia cells, understand the mechanisms promoting disease progression, identify new therapeutic targets and/or develop new strategies to overcome resistance to imatinib treatment.

We are interested to study the molecular mechanisms responsible for progression of chronic myeloid leukemia (CML) as well as signaling pathways promoting development of the resistance to therapy. Especially, we are interested to investigate the prosurvival pathways involved in the regulation of cellular stress response, chromosomal instability and aneuploidy. We are also looking for novel, prospective targets for CML therapy as well as alternative mechanisms to induce cell death in apoptosis-resistant cells. We are convinced that a search for new therapeutic strategies for CML must target signalling pathways necessary for cancer survival.

 

 

Currently we investigate:

  1. Role of  the Unfolded Protein Response and the PERK-eIF2alpha- dependent signaling in leukemia development, progression and resistance to therapy (in vitro and in vivo studies)
  2. Mechanisms leading to genomic instability of CML cells; the role of BRCA1
  3. Mechanism of BRCA1 downregulation in leukemia
  4. Role and mechanisms of leukemia-stroma interactions
  5. Role of the secretome in CML development and progression; miRNA and proteins studies
  6. Alternative cell death mechanisms to overcome resistance to apoptosis in cancer cells; induction of mitotic catastrophy

 

In our studies we use a diverse array of techniques, ranging from biochemical and molecular biology methods to cellular biology,  cytometry and microscopy techniques, including confocal, EM, SEM, light sheet and spinning disc microscopy to visualize cellular processes and molecules.

 

 

Selected Papers:

(All papers available at the PUBLICATIONS Tab):

  1. Nieborowska-Skorska M, Sullivan K, Dasgupta Y, Podszywalow-Bartnicka P, Hoser G, Maifrede S, Martinez E, Di Marcantonio D, Bolton-Gillespie E, Cramer-Morales K, Lee J, Li M, Slupianek A, Gritsyuk D, Cerny-Reiterer S, Seferynska I, Stoklosa T, Bullinger L, Zhao H, Gorbunova V, Piwocka K, Valent P, Civin CI, Muschen M, Dick JE, Wang JC, Bhatia S, Bhatia R, Eppert K, Minden MD, Sykes SM, Skorski T. Gene expression and mutation-guided synthetic lethality eradicates proliferating and quiescent leukemia cells. J Clin Invest. 2017 Jun 1;127(6):2392-2406. doi: 10.1172/JCI90825.
  2. Wolczyk M, Podszywalow-Bartnicka P, Bugajski L, Piwocka K. Stress granules assembly affects detection of mRNA in living cells by the NanoFlares; an important aspect of the technology. Biochim Biophys Acta. 2017 May;1861(5 Pt A):1024-1035. doi: 10.1016/j.bbagen.2017.02.010.
  3. Bieńkowska A, Kiernozek E, Kozlowska E, Bugajski Ł, Drela N. A new approach to the role of IL-7 and TGF-ß in the in vitro generation of thymus-derived CD4+CD25+Foxp3+ regulatory T cells. Cytokine. 2017 Aug 18. pii: S1043-4666(17)30219-3. doi: 10.1016/j.cyto.2017.07.019.
  4. Podszywalow-Bartnicka P, Cmoch A, Wolczyk M, Bugajski L, Tkaczyk M, Dadlez M, Nieborowska-Skorska M, Koromilas A, Skorski T, Piwocka K. Increased phosphorylation of eIF2α in chronic myeloid leukemia cells stimulates secretion of matrix modifying enzymes. Oncotarget  2016  Oct 27. doi: 10.18632/oncotarget.12941.
  5. Mamińska A, Bartosik A, Banach-Orłowska M, Pilecka I, Jastrzębski K, Zdżalik-Bielecka D, Castanon I, Poulain M, Neyen C, Wolińska-Nizioł L, Toruń A, Szymańska E, Kowalczyk A, Piwocka K, Simonsen A, Stenmark H, Fürthauer M, González-Gaitán M, Miaczynska M. ESCRT proteins restrict constitutive NF-κB signaling by trafficking cytokine receptors. Sci Signal. 2016 Jan 19;9(411):ra8. doi: 10.1126/scisignal.aad0848
  6. Wylot B, Konarzewska K, Bugajski L, Piwocka K, Zawadzka M. Isolation of vascular endothelial cells from intact and injured murine brain cortex-technical issues and pitfalls in FACS analysis of the nervous tissue. Cytometry A. 2015 Oct;87(10):908-20.. doi: 10.1002/cyto.a.22677
  7. Podszywalow-Bartnicka P, Wolczyk M, Kusio-Kobialka M, Wolanin K, Skowronek K, Nieborowska-Skorska M, Dasgubta Y, Skorski T, Piwocka K. Downregulation of BRCA1 protein in BCR-ABL1 leukemia cells depends on stress-triggered TIAR-mediated suppression of translation. Cell Cycle 2014 Dec.1;13(23): 3727-41. doi:10.4161/153841012014.965013
  8. Piwocka K, Dekker FJ. Inhibition of p53 acetylation by PCAF inhibitor anacardic acid derivative in BCR-ABL1-expressing cells.;  breaking resistance to DNA damage and possible therapeutical implications.  World Biomedical Frontiers; Cancer- 2014-3-8. ISSN, 2328-0166
  9. Cmoch A, Podszywalow-Bartnicka P, Palczewska M, Piwocka K, Groves P, Pikula S. Stimulators of mineralization limit the invasive phenotype of human osteosarcoma cells by a mechanism involving impaired invadopodia formation. PLoS One 2014 Oct 14;9(10):e109938. doi: 10.1371/journal.pone.0109938.
  10. Kusio-Kobialka M, Dudka-Ruszkowska W, Ghizzoni M, Dekker FJ, Piwocka K. Inhibition of PCAF by anacardic acid derivatives leads to apoptosis and breaks resistance to DNA damage in BCR-ABL-expressing cells. Anticancer Agents Med Chem. 2013 Jun;13(5):762-7.
  11. Kusio-Kobialka M, Podszywalow-Bartnicka P, Peidis P, Glodkowska-Mrowka E, Wolanin K, Leszak G, Seferynska I, Stoklosa T, Koromilas AE, Piwocka K. The PERK-eIF2alpha phosphorylation arm is a prosurvival pathway of BCR-ABL signaling and confers resistance to imatinib treatment in chronic myeloid leukemia cells. Cell Cycle. 2012 Nov 1;11(21):4069-78.
  12. Kusio-Kobialka M, Wolanin K, Podszywalow-Bartnicka P, Sikora E, Skowronek K, McKenna SL, Ghizzoni M, Dekker FJ, Piwocka K. Increased acetylation of lysine 317/320 ofp53 caused by BCR-ABL protects from cytoplasmic translocation of p53 and mitochondria-dependent apoptosis in response to DNA damage. Apoptosis 2012; 17(9):950-63.
  13. Piwocka K., Wolanin K., Kusio-Kobialka M., Podszywalow-Bartnicka P. Bcr-Abl hits at mitosis; implications for chromosomal instability, aneuploidy and therapeutic strategy. Myeloid Leukemia – Basic Mechanisms of Leukemogenesis", 2011 InTech  ISBN 978-953-789-5
  14. Wolanin K, Magalska A, Kusio-Kobialka M, Podszywalow-Bartnicka P, Vejda S, McKenna SL, Mosieniak G, Sikora E, Piwocka K. Expression of oncogenic kinase Bcr-Abl impairs mitotic checkpoint and promotes aberrant divisions and resistance to microtubule-targeting agents. Mol Cancer Ther. 2010 May;9(5):1328-38.
  15. Podszywalow-Bartnicka P, Kosiorek M, Piwocka K, Sikora E, Zablocki K, Pikula S. Role of annexin A6 isoforms in catecholamine secretion by PC12 cells: distinct influence on calcium response. J Cell Biochem. 2010 Sep 1;111(1):168-78.
  16. O’Sullivan-Coyne G, O’Sullivan GC, O’Donovan TR, Piwocka K, McKenna SL. Curcumin induces apoptosis-independent death in oesophageal cancer cells. Br J Cancer. 2009 Nov 3;101(9):1585-95.
  17. Wolanin K, Magalska A, Mosieniak G, Klinger R, McKenna S, Vejda S, Sikora E, Piwocka K. Curcumin affects components of the chromosomal passenger complex and induces mitotic catastrophe in apoptosis-resistant Bcr-Abl-expressing cells. Mol Cancer Res. 2006 Jul;4(7):457-69.
  18. Piwocka K, Vejda S, Cotter TG, O'Sullivan GC, McKenna SL. Bcr-Abl reduces endoplasmic reticulum releasable calcium levels by a Bcl-2-independent mechanism and inhibits calcium-dependent apoptotic signaling. Blood. 2006 May 15;107(10):4003-10.