Leukaemia Biology

Leukaemia Biology

The aim of our programme is to identify key common events which contribute to the molecular pathogenesis of myeloproliferative disorders and myeloid leukaemias thereby developing new understanding of transformation processes and how they may be disrupted.

 

Haematopoiesis is a precisely regulated hierarchical process. Haematopoietic stem cells are pluripotent, can undergo self-renewal and differentiate to developmentally restricted progenitor cells that eventually form mature blood cells. The myeloid leukaemias (including the myeloproliferative neoplasms) are diseases where the process of self-renewal and differentiation are disrupted. Recent years have seen elucidation of mutational events associated with these diseases and some mechanistic detail associated with transformation. Chromosomal translocations, gene rearrangements and point mutations have all been identified which are associated with leukaemogenesis. In the context of the myeloid leukaemias one effect of these genetic changes is activation of protein tyrosine kinases (PTKs) including ABL, FLT3, KIT and PDGFαR.

OncogeneDiseaseTranslocation/Mutation
BCR/ABLChronic Myeloid Leukaemiat(9;22)(q34;q11)
FLT-3 ITDAcute Myelod LeukaemiaInternal Tandem Duplication
NPM-ALKAnaplastic Large Cell Lymphomat(2;5)(p23;q35)
Tel/PDGFβRChronic Myelomonocytic Leukaemiat(5;12)(q33;p13)
FIP1L1/PDGFαRHyperosinophilic syndromeInterstitial deletion on chromosome 4q12M
Kit 816V mutantMast Cell Leukaemia and othersActivating mutation D816V
JAK2 mutantsChronic Myeloproliferative Disorder Polycythemia veraV617F and K562L
MPL mutants (Thrombopoietin receptor)Myelofibrosis with thrombocytosisW515L

Activation of the PTKs can result from point mutations, reciprocal chromosomal translocations and internal tandem duplication; thus in Anaplastic Large Cell Lymphoma (ALCL) the t(2:5) translocation leads to the formation of the NPM/ALK gene which encodes a lymphoma specific NPM/ALK protein with intrinsic and disregulated PTK activity. A point mutation in the Kit PTK, D816V, is associated with transformation in mast cell leukaemia and in the myeloproliferative disorders the t(9;22) translocation found within Chronic Myeloid Leukaemia (CML) leads to the production of the BCR/ABL oncogenic PTK. Similarly, Fip1L/PDGFαR PTK is associated with the pathogenesis of about 50% of patients with the hypereosinophilic syndrome. The internal tandem duplication found in Flt3 PTK (Flt3ITD) has been associated with over 20-30% of acute myeloid leukaemia (AML) cases, the Flt3 gaining dis-regulated kinase activity resultant from this insertional mutagenic event. A key feature of the leukaemias and lymphomas is their progressive nature and thus an important question is whether these kinases share a common mode of action?

Whilst targeted therapies such as the paradigmatic use of imatinib in treatment of CML has altered the landscape in oncology research, the treatment does not eradicate the disease and problems still persist not least from the survival of the quiescent leukemic stem cell. Many of the front line drugs in leukaemia treatment target the committed progenitors. The most desirable target is the quiescent stem cells as removal of this would ensure the irradiation of the disease. Thus finding novel and common targets in leukaemias and lymphomas may improve treatment strategies.

No systematic analysis of the effects of these leukaemogenic tyrosine kinases has been undertaken and we have no clear idea on the commonalities or peculiarities of signalling from each transforming tyrosine kinase. The Broad aim of our programme of research has been to identify key common events which contribute to the molecular pathogenesis of myeloproliferative disorders and myeloid leukaemias thereby developing new understanding of transformation processes and how they may be disrupted. Seeking common effectors for leukaemogenic PTKs is of value in discerning potential new targets in rare and more common diseases. We addressed this problem with a systems biology approach and as such have produced large data sets on the nine leukaemogenic oncogenes in the table above. The data sets consists of gene array profiling and proteomic and phosphoproteomic data sets of whole cell lysates, nuclear and cytoplasmic fractions. Integrated analysis of all these data sets is allowing us to identify key common events which contribute to the molecular pathogenesis of myeloproliferative disorders and myeloid leukaemias.