Research Profile

Karen Keeshan

Biography

Research Interests

Leukemia occurs when genes involved in proliferation and differentiation pathways in haematopoietic cells are perturbed. When these genes affect the myeloid lineage, the result is myeloid leukemias (e.g. Chronic Myeloid Leukemia (CML), Acute Myeloid Leukemia (AML)), and when these genes affect the lymphoid lineage the result is lymphoid leukemias (e.g. T-ALL, B-ALL (T and B cell-acute lymphoblastic leukemia).

The Keeshan laboratory focuses on oncogenes and transcription factors, and their relationship to differentiation of haematopoietic stem cells into different specific lineages in normal and leukemic cells.

The primary focus of the laboratory is on myeloid leukemias and the recently identified Trib2 oncogene. Trib2 is a member of the Trib family of serine/threonine kinases homologous proteins (Trib1, Trib2, Trib3). This family of proteins is currently thought to function as pseudokinases as no kinase activity had been ascribed to date. Trib1 and Trib2 are both associated with human AML. One of the goals of Dr. Keeshan's research is to understand the normal function of Trib2 and how Trib2 contributes/causes AML.

Another focus of the laboratory is to understand how transcription factors function during haematopoietic development and disease, and how these factors are perturbed by oncogenes. A critical transcription factor involved in granulocytic cell development is C/EBPalpha, which is the founding member of the C/EBP family of bZIP transcription factors. C/EBPalpha mutation/disruption is associated with CML and AML, and can occur through oncogenes such as BCR-ABL, AML1-ETO, and Trib2. Dr. Keeshan is interested in understanding the deregulation of such transcription factors by oncogenes.

The multistep pathogenesis model of AML hypothesizes that cooperation of at least two broad classes of mutation must occur for blastic transformation i.e. both differentiation genes and proliferation/survival genes. Another goal of Dr. Keeshan's research is to understand what genes can cooperate with Trib2 in AML. The models used to interrogate this include a directed approach using retroviral insertion analysis, and a predictive approach using known oncogenes.

A range of techniques are used including retroviral gene transfer and bone marrow transplant models, flow cytometry, and molecular and biochemical techniques.

Research in the laboratory is supported by funding from:
  • Science Foundation Ireland - President of Ireland Young Investigator Award (SFI-PIYRA)
  • The Leukemia and Lymphoma Society.
  • Marie Curie EU-FP7-PEOPLE-IRG
  • IRCSET.

Publications

Peer Reviewed Journals

 YearPublication
(2015)'Knockdown of interleukin-1 receptor 1 is not neuroprotective in the 6-hydroxydopamine striatal lesion rat model of Parkinson's disease'
Walsh S, Gavin A, Wyatt S, O'Connor C, Keeshan K, Nolan YM, O'Keeffe GW*, Sullivan AM*. (2015) 'Knockdown of interleukin-1 receptor 1 is not neuroprotective in the 6-hydroxydopamine striatal lesion rat model of Parkinson's disease'. International Journal of Neuroscience, 125 (1):70-77 [Details]
(2013)'Negative regulation of TLX by IL-1β correlates with an inhibition of adult hippocampal neural precursor cell proliferation'
Ryan SM, O'Keeffe GW, O'Connor C, Keeshan K, Nolan YM. (2013) 'Negative regulation of TLX by IL-1β correlates with an inhibition of adult hippocampal neural precursor cell proliferation'. Brain Behav Immun, 33 :7-13 [Details]
(2013)'Tribbles in acute leukemia'
Liang, KL,Rishi, L,Keeshan, K (2013) 'Tribbles in acute leukemia'. Blood, 121 :4265-4270 [DOI] [Details]
(2012)'Elevated TRIB2 with NOTCH1 activation in paediatric/adult T-ALL'
Hannon, MM,Lohan, F,Erbilgin, Y,Sayitoglu, M,O'Hagan, K,Mills, K,Ozbek, U,Keeshan, K (2012) 'Elevated TRIB2 with NOTCH1 activation in paediatric/adult T-ALL'. British Journal of Haematology, 158 :626-634 [DOI] [Details]
(2008)'Tribbles homolog 2 (Trib2) and HoxA9 cooperate to accelerate acute myelogenous leukemia'
Keeshan K, Shestova O, Ussin L, Pear WS; (2008) 'Tribbles homolog 2 (Trib2) and HoxA9 cooperate to accelerate acute myelogenous leukemia'. Blood Cells Mol Dis, 40 (1):119-121 [DOI] [Details]
(2007)'Distinct gene expression profiles of acute myeloid/T-lymphoid leukemia with silenced CEBPA and mutations in NOTCH1'
Wouters BJ, Jordà MA, Keeshan K, Louwers I, Erpelinck-Verschueren CA, Tielemans D, Langerak AW, He Y, Yashiro-Ohtani Y, Zhang P, Hetherington CJ, Verhaak RG, Valk PJ, Löwenberg B, Tenen DG, Pear WS, Delwel R; (2007) 'Distinct gene expression profiles of acute myeloid/T-lymphoid leukemia with silenced CEBPA and mutations in NOTCH1'. Blood, 110 (10):3706-3714 [DOI] [Details]
(2006)'The tumor suppressor menin regulates hematopoiesis and myeloid transformation by influencing Hox gene expression'
Chen YX, Yan J, Keeshan K, Tubbs AT, Wang H, Silva A, Brown EJ, Hess JL, Pear WS, Hua X; (2006) 'The tumor suppressor menin regulates hematopoiesis and myeloid transformation by influencing Hox gene expression'. Proceedings of The National Academy of Sciences of The United States of America, 103 (4):1018-1023 [DOI] [Details]
(2006)'Leukemogenesis induced by wild-type and STI571-resistant BCR/ABL is potently suppressed by C/EBPalpha'
Ferrari-Amorotti G, Keeshan K, Zattoni M, Guerzoni C, Iotti G, Cattelani S, Donato NJ, Calabretta B; (2006) 'Leukemogenesis induced by wild-type and STI571-resistant BCR/ABL is potently suppressed by C/EBPalpha'. Blood, 108 (4):1353-1362 [DOI] [Details]
(2006)'Tribbles homolog 2 inactivates C/EBPalpha and causes acute myelogenous leukemia'
Keeshan K, He Y, Wouters BJ, Shestova O, Xu L, Sai H, Rodriguez CG, Maillard I, Tobias JW, Valk P, Carroll M, Aster JC, Delwel R, Pear WS; (2006) 'Tribbles homolog 2 inactivates C/EBPalpha and causes acute myelogenous leukemia'. Cancer Cell, 10 (5):401-411 [DOI] [Details]
(2006)'The requirement for Notch signaling at the beta-selection checkpoint in vivo is absolute and independent of the pre-T cell receptor'
Maillard I, Tu L, Sambandam A, Yashiro-Ohtani Y, Millholland J, Keeshan K, Shestova O, Xu L, Bhandoola A, Pear WS; (2006) 'The requirement for Notch signaling at the beta-selection checkpoint in vivo is absolute and independent of the pre-T cell receptor'. The Journal of Experimental Medicine, 203 (10):2239-2245 [DOI] [Details]
(2003)'Bcr-Abl upregulates cytosolic p21(WAF-1/CIP-1) by a phosphoinositide-3-kinase (PI3K)-independent pathway'
Keeshan, K,Cotter, TG,McKenna, SL; (2003) 'Bcr-Abl upregulates cytosolic p21(WAF-1/CIP-1) by a phosphoinositide-3-kinase (PI3K)-independent pathway'. Rna-A Publication of The Rna Society, 123 :34-44 [Details]
(2003)'Bcr-Abl upregulates cytosolic p21WAF-1/CIP-1 by a phosphoinositide-3-kinase (PI3K)-independent pathway'
Keeshan, K; Cotter, TG; McKenna, SL; (2003) 'Bcr-Abl upregulates cytosolic p21WAF-1/CIP-1 by a phosphoinositide-3-kinase (PI3K)-independent pathway'. British Journal of Haematology, 123 (1):983-992 [Details]
(2003)'Transcription activation function of C/EBPalpha is required for induction of granulocytic differentiation'
Keeshan K, Santilli G, Corradini F, Perrotti D, Calabretta B; (2003) 'Transcription activation function of C/EBPalpha is required for induction of granulocytic differentiation'. Blood, 102 (4):1267-1275 [DOI] [Details]
(2002)'High Bcr-Abl expression prevents the translocation of Bax and Bad to the mitochondrion'
Keeshan, K; Cotter, TG; McKenna, SL; (2002) 'High Bcr-Abl expression prevents the translocation of Bax and Bad to the mitochondrion'. Leukemia, 16 (9):1725-1734 [Details]
(2002)'High Bcr-Abl expression prevents the translocation of Bax and Bad to the mitochondrion'
Keeshan, K,Cotter, TG,McKenna, SL; (2002) 'High Bcr-Abl expression prevents the translocation of Bax and Bad to the mitochondrion'. Official Journal of The Leukemia Society of America, 16 :1725-1734 [DOI] [Details]
(2001)'Elevated Bcr-Abl expression levels are sufficient for a haematopoietic cell line to acquire a drug-resistant phenotype'
Keeshan, K,Mills, KI,Cotter, TG,McKenna, SL; (2001) 'Elevated Bcr-Abl expression levels are sufficient for a haematopoietic cell line to acquire a drug-resistant phenotype'. Official Journal of The Leukemia Society of America, 15 :1823-1833 [Details]
(2001)'Elevated Bcr-Abl expression levels are sufficient for a haematopoietic cell line to acquire a drug-resistant phenotype'
Keeshan, K; Mills, KI; Cotter, TG; McKenna, SL; (2001) 'Elevated Bcr-Abl expression levels are sufficient for a haematopoietic cell line to acquire a drug-resistant phenotype'. Leukemia, 15 (12):1823-1833 [Details]
(2000)'Molecular abnormalities in Chronic Myeloid Leukaemia : Deregulation of cell growth and apoptosis'
Keeshan K, Di Bacco A, McKenna SL, Cotter TG; (2000) 'Molecular abnormalities in Chronic Myeloid Leukaemia : Deregulation of cell growth and apoptosis'. The oncologist, 5 :405-415 [Details]

Abstract

 YearPublication
(2013)NFIX EXPRESSION CRITICALLY MODULATES EARLY B LYMPHOPOIESIS AND MYELOPOIESIS.
Keeshan, K,O'Connor, C,Campos, J,Murphy, B,Hannon, M,Michie, A (2013) NFIX EXPRESSION CRITICALLY MODULATES EARLY B LYMPHOPOIESIS AND MYELOPOIESIS. Abstract [Details]
(2013)E2F1 POSITIVELY REGULATES TRIB2 PSEUDOKINASE EXPRESSION AND PROLIFERATION IN ACUTE LEUKAEMIA.
Keeshan, K,Hannon, M,Rishi, L,Hasemann, M,Frank, AK,Timoney, J,O'Connor, C,Cahill, M,Porse, B (2013) E2F1 POSITIVELY REGULATES TRIB2 PSEUDOKINASE EXPRESSION AND PROLIFERATION IN ACUTE LEUKAEMIA. Abstract [Details]
(2012)Elevated Trib2 with Notch1 activation in pediatric/adult T-ALL.
Hannon, M,Lohan, F,Erbilgin, Y,O'Hagan, K,Mills, K,Ozbek, U,Keeshan, K (2012) Elevated Trib2 with Notch1 activation in pediatric/adult T-ALL. Abstract [Details]
(2012)Mechanism of Trib2 mediated degradation of C/EBP-alpha in acute myelogenous leukaemia.
Lohan, FM,Keeshan, K (2012) Mechanism of Trib2 mediated degradation of C/EBP-alpha in acute myelogenous leukaemia. Abstract [Details]
(2011)Regulation of Trib2 gene expression in normal and AML cells.
Hannon, M,Al-Shahrour, F,Ebert, BL,Keeshan, K (2011) Regulation of Trib2 gene expression in normal and AML cells. Abstract [Details]
(2010)Degradation of C/EBPalpha by Trib proteins correlates with Trib mediated acute myeloid leukemia.
Keeshan, K (2010) Degradation of C/EBPalpha by Trib proteins correlates with Trib mediated acute myeloid leukemia. Abstract [Details]
(2008)Trib1 and Trib2 but Not Trib3 Degrade C/EBP alpha and Induce Acute Myelogenous Leukemia.
Dedhia, P,Keeshan, K,Vega, M,Uljon, S,Xu, LW,Shestova, O,Romany, C,Blacklow, SC,Pear, WS (2008) Trib1 and Trib2 but Not Trib3 Degrade C/EBP alpha and Induce Acute Myelogenous Leukemia. Abstract [Details]

Other

 YearPublication
(2008)Trib1 and Trib2 But Not Trib3 Degrade C/Ebp Alpha and Induce Acute Myelogenous Leukemia.
Dedhia, P, Keeshan, K, Vega, M, Uljon, S, Xu, LW, Shestova, O, Romany, C, Blacklow, SC, Pear, WS; (2008) Trib1 and Trib2 But Not Trib3 Degrade C/Ebp Alpha and Induce Acute Myelogenous Leukemia. Other [Details]

Professional Activities

Professional Associations

 AssociationFunctionFrom / To
American Society of Hematology (ASH). Member/
European Hematology Association (EHA). Member/
Irish Association for Cancer Research. Committee Member/

Patents

 Patent NumberTitleInventorGranted
S-4025Diagnostic and Therapeutic Utility of Tribbles-2 in human cancers Keeshan K, He Y, Pear WS01-JAN-06

Conference Contributions

 YearPublication
(2012)7th Neuroscience Ireland Conference,
Walsh S, Keeshan K, Nolan Y, O’Keeffe GW, Sullivan AM. (2012) The effect of IL-1R1 shRNA intra-nigral administration in a hemi-parkinsonian 6-hydroxydopamine rat model. [Poster Presentation], 7th Neuroscience Ireland Conference, Dublin, Ireland , 05-SEP-12 - 06-SEP-12. [Details]
(2008)PhD scholars programme in Cancer Biology Launch,
Keeshan, K.; (2008) PhD scholars programme in Cancer Biology Launch. [Oral Presentation], PhD scholars programme in Cancer Biology Launch, University College Cork , 03-OCT-08 - 03-OCT-08. [Details]
(2007)The 674th Biochemical Society Meeting : Signalling Homeostasis,
Keeshan, K.; (2007) Relationship between variable Bcr-Abl expression levels and drug resistance : Role of AKT/PKB pathway. [Oral Presentation], The 674th Biochemical Society Meeting : Signalling Homeostasis, Dublin, Ireland , 01-JUL-07 - 01-JUL-07. [Details]
(2007)Seventh International Workshop on Molecular Aspects of Myeloid Stem Cell Development and Leukaemia,,
Keeshan, K.; (2007) Tribbles homolog 2 (Trib2) inactivates C/EBPalpha and causes acute myeloid leukaemia. [Oral Presentation], Seventh International Workshop on Molecular Aspects of Myeloid Stem Cell Development and Leukaemia,, , 01-MAY-07 - 01-MAY-07. [Details]
(2006)48th Annual meeting and exposition of the American Society of Hematology (ASH),
Keeshan, K.; (2006) Tribbles homolog 2 (Trib2) inactivates C/EBPalpha and causes acute myeloid leukaemia. [Oral Presentation], 48th Annual meeting and exposition of the American Society of Hematology (ASH), Florida, USA , 01-DEC-06 - 01-DEC-06. [Details]

Committees

 CommitteeFunctionFrom / To
Irish Association for Cancer Research /
Journal reviewer: Stem Cells /
Organiser and sub-group member for The Translational Research Conference, UCC, June 2009 /

Employment

 EmployerPositionFrom / To
University College Cork SFI-PIYRA Principal Investigator01-JUL-08 /
University of Pennsylvania, Philadelphia, USA Postdoctoral Special Fellow01-JAN-07 / 30-JUN-08
University of Pennsylvania, Philadelphia, USA Postdoctoral Fellow01-JAN-03 / 01-JAN-07
Thomas Jefferson Unviversity, Kimmel Cancer Centre, USA Postdoctoral researcher01-JAN-02 / 01-JAN-03

Education

 YearInstitutionQualificationSubject
1998University College Cork BSCBiochemistry
2001University College Cork PHDScience

Teaching Activities

Teaching Interests

Contact details

Search profiles by name

Search profiles by topic

School of Biochemistry and Cell Biology

Scoil na Bithcheimice agus na Cillbhitheolaíochta

University College Cork, Western Road, Cork.

Top