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PhD by Research Programme (Funded Research Programme - Chromosome and Genome Biology)

Employer
Global Academy Jobs
Location
Singapore
Closing date
Jan 31, 2017

Job Details

Research Project Title: Understanding Molecular Mechanisms of Clonal Evolution in Childhood Leukaemia

Source of Funding: MOE Tier 2 Grant

Principal Investigator: Professor Dean Nizetic

Project Description:

Acute leukaemias are the most common childhood cancers, affecting up to 100 new children in Singapore yearly. Children with Down’s Syndrome (DS) have 50-100 fold higher incidence of leukaemias than normal children, including all types of (i) acute myeloid leukaemia (AML) and (ii) B-cell acute lymphocytic leukaemia (ALL), and (iii) have unique disease history that enables the study of stages of cancer evolution. Using unique advantages of this model, we propose testing specific hypotheses on mechanisms governing the biology of clonal leukaemic evolution.

Acute megakaryoblastic leukaemia (AMKL), which in DS is preceded by transient myeloproliferative disorder (TMD), has a 500 fold increased incidence relative to euploid children8. TMD is a self-regressing pre-leukaemic state, that affects up to 15% of DS neonates, has all the hallmarks of true AMKL, but regresses spontaneously (without any treatment) within 3 months after birth. In 25-30% of cases it returns in the same child 2-5 years later as a full-blown AMKL that is lethal if untreated9. B-cell acute lymphoblastic leukaemia (B-ALL), the most frequent overall childhood cancer in Singapore, acquires trisomy 21 (T21, the genetic cause of DS) in clonal evolution as one of the commonest sole karyotypic changes10. The B-ALL is also 20-50 fold more frequent in DS children9. Using unique advantages of the DS leukaemia as a disease-model, we propose testing specific hypotheses on mechanisms governing the biology of clonal leukaemic evolution for both ALL and AML in general.

Recent breakthrough achievements by the P.I. with potential for advancing knowledge in DS-leukaemias
The nature of acquired oncogenic driver events have recently been discovered for both DS-AMKL and DS-ALL in the exome-sequencing studies co-directed by the P.I.:

(i) The overall spectrum of driver mutations in DS-AMKL and DS-ALL was found to be similar to non-DS childhood AMKL and ALL, respectively27-29, with exception of the GATA1 mutation.

(ii) For DS-ALL, CRLF2, JAK2 and RAS mutations were predominant leukaemia drivers. RAS
mutations were found to be completely mutually exclusive with JAK2 mutations (P<0.016), driving a combined total of 70% of analysed DS-ALL cases27. This mutual exclusion held true also when reexamining other studies on DS-AMKL and non-DS leukaemias27,29,30.

(iii) For clonal evolution from DS-TMD to DS-AMKL, the exomesequencing did not find a common, recurrently mutated driver gene, but found that cohesin-proteincomplex (Rad21, Stag2, Smc3) were the most recurrent functionally related mutations28,29. 

(iv) The P.I. has recently generated a unique induced-pluripotent-stem-cell (hiPSC) model system for DS, by re-programming primary cells from a person mosaic for DS (confirmed not to have had TMD or leukaemia), and cloning separately multiple trisomy 21 (T21) and normal (D21) iPSC lines that are otherwise isogenic (see Murray et al Stem Cells 2015). We show that T21 iPSC have a significantly greater propensity to produce haematopoietic stem cells (HSC) than isogenic D21 controls, reproducing recently published data on DS hiPSCs, and primary foetal liver (FL) cells.

Approach and Aims 

De-regulation of chromatin-remodelling complexes, including Polycomb-Repressor-Complex-2 (PRC2), by constitutional T21 (DS) or acquired T21 (in non-DS ALL) is an important pathogenic component in childhood leukaemia clonal progression. We will examine the effects of canonical and non-canonical PRC2 actions on proliferation of CMK (a primary DS-AMKL line), a model CRLF2-JAK2 mutation-engineered pro-B cell line we constructed, primary DS-TMD and ALL samples, and primary non-DS ALL (+/- acquired T21), from Italian Association of Paediatric Haematology Oncology (AIEOP, collaborator GB) and Malaysia-Singapore-ALL-study (Co-I AEJY and collaborator HA), as well as iPSC-derived haematopoietic stem/progenitor cells.

We have cryopreserved primary cells from multiple DS-TMD, DS-AMKL and DS-ALL cases, at acute, remission and relapse stages, as well as a freshly acquired CD34+ umbilical cord blood cells from a DS newborn without obvious TMD. We will generate hiPSCs from European, Malay and Chinese-Singaporean DS-TMD samples, from individuals +/– for development of subsequent DSAMKL or DS-ALL. We will pilot test these iPSCs for feasibility as an in vitro model of DS-leukaemia.

Collaborations and International placement

Nizetic lab actively collaborates on multiple projects with 9 labs/clinics in Singapore and 17 labs/clinics in Europe and U.S.A. For this project, a possibility exists (which is not obligatory) of organizing a placement for 12-18 months in a collaborating lab in UK.

If you have questions regarding this project, please email the Principal Investigator, Professor Dean Nizetic, d.nizetic@ntu.edu.sg 

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