1. Leukaemia in
Down’s Syndrome

2. Overview
• Down’s Syndrome
• Leukaemia
• The link between Down’s Syndrome and Leukaemia
• Epidemiology
• Aetiology
• Future research
• Implications for other leukaemias
• Treatment

3. Down’s Syndrome
 Originally described in 1866
 Associated with Trisomy 21 in 1959
 Prevalence 1/1000 births
 95% due to chromosomal non-disjunction; 5% due to translocations
 Risk factors:
 increased maternal age
 1/1000 maternal age 30 years
 9/1000 maternal age 40 years
 ?infertility treatment

4.  Clinical Features
 physical appearance
 intellectual disability
 developmental delay
 sensory abnormalities
 congenital heart disease
 Alzheimer’s Disease
 GI malformations
 thyroid disorders
 poor immune system
 LEUKAEMIA
Down’s Syndrome

5. Leukaemia
 cancer
 WBC proliferation in the bone
marrow
 Classification:
 acute/chronic
 type of WBC
Current leukaemia model:
 2 co-operating mutations
 1 leading to impaired
differentiation
 1 leading to increased
proliferation/cell survival
Picture: Hitzler & Zipursky, 2005

6. Leukaemia
 Acute lymphoblastic leukaemia (ALL)
 derived from B lymphocyte or T lymphocyte precursors
 80% childhood leukaemia
 Acute myeloid leukaemia (AML)
 e.g. myeloid, monocytic, megakaryocytic, erythroid
 20% childhood leukaemia
 Acute megakaryoblastic leukaemia (AMKL)
 AML subtype: leukaemic cells have platelet precursor phenotype
 6% childhood AML cases

7. Leukaemia in Down’s Syndrome
 10-20 fold increased risk of leukaemia
 ALL
 80% childhood leukaemia; 60% Down’s Syndrome leukaemia
 20 times higher incidence children with Down’s Syndrome compared to
children without Down’s Syndrome
 AML
 20% childhood leukaemia; 40% Down’s Syndrome leukaemia
 AMKL
 6% childhood AML; 62% Down’s Syndrome AML
 500 times higher incidence children with Down’s Syndrome compared to
children without Down’s Syndrome

8. Leukaemia in Down’s Syndrome
AML in Down’s Syndrome
 AMKL in most cases
 younger median age of onset
 2 in Down’s Syndrome
 8 in non-Down’s Syndrome
 myelodysplastic syndrome more common prior to leukaemia
 Transient Leukaemia

9. Transient Leukaemia
Also termed: ‘Transient Abnormal Myelopoiesis’ and ‘Transient Myeloproliferative
Disorder’
 10% newborn infants with Down’s Syndrome
 peripheral blood contains clonal population of megakaryoblasts
 cannot be distinguished from AMKL blasts by routine methods
 usually clinically silent
 usually disappear within 3 months
 majority of cases totally resolve
However
 can be fatal
 20% develop MDS and AMKL by the age of 4 years

10. Transient Leukaemia
Leukaemic cells in Transient Leukaemia and AMKL can:
 show variable megakaryocytic differentiation
 show features of multiple haematopoietic lineages
Evidence that Transient Leukaemia is a precursor for AMKL
 near identical morphology, immunophenotype, ultrastructure
 clone-specific GATA1 mutations
 GATA1: X chromosome, ‘zinc-finger’ transcription factor, essential for
differentiation of megakaryocytic, erythroid and basophillic lineages
 therefore have common cell of origin
Leukaemic cells in Transient Leukaemia and AMKL in Down’s Syndrome can form
megakaryocytic, erythroid or basophillic lineages

11. GATA1
 all Transient Leukaemia and AMKL cases have GATA1 mutations
 most abrogate splicing of exon 2 or produce stop codon prior to alternative
start codon at position 84
 lack N-terminal domain
 mutations disappear upon remission
 disease specific mutations
 leukemogenisis model: transcription factor mutation blocks differentiation
 GATA1 mutation determines haematopoietic lineage
 GATA1 mutations present in Transient Leukaemia at birth
 mutations in utero
 proportion of Down’s Syndrome fetuses acquire GATA1 mutation
 large clone = Transient Leukaemia
 small clone = no clinical signs

12. Aetiology
Three distinct steps:
1) fetal heamatopoietic cell with trisomy 21
 rare Transient Leukaemia cases in people without Down’s syndrome
 acquired trisomy 21 only in haematopoietic cells
1) mutation of GATA1
 expression of shortened
GATA1 (GATA1s)
1) extra, as of yet unknown event
 not all cases of Transient
Leukaemia progress to AMKL
Picture: Hitzler & Zipursky, 2005

13. Aetiology
Transient
Leukaemia
with clinical
signs of
disease
?Transient
Leukaemia
with no
clinical signs
of disease
Picture: Ahmed et al, 2004

14. Future Research
Loss of GATA1 function in people without Down’s Syndrome results in:
 accumulation of abnormally differentiated megakaryocytes
 thrombocytopenia
 NO LEUKAEMIC TRANSFORMATION
 discovered by Shivdasani et al, 1997
 What is the effect of Trisomy 21?
 What ‘advantage’ does GATA1 mutation provide to people with
Down’s Syndrome?
What is the ‘second-hit’?

15. Implications for other leukaemias
 current acute leukaemia model:
 2 co-operating mutations
 1 leading to impaired differentiation
 1 leading to increased proliferation/cell survival
This means that that the sequence of Transient Leukaemia to
AMKL as seen in Down’s Syndrome is a chance to investigate this
model of leukaemia and discover the timing and nature of the 2
necessary events.

16. Treatment of Leukaemia in Down’s Syndrome
AML (AMKL)
 increased sensitivity to cytarabine
 80% 5 year survival
 failure usually due to toxicity (mucositis and infection)
ALL
 similar treatment as in AML
 60-70% cure rate (75-85% in population without Down’s Syndrome)
 no increased sensitivity, but increased toxicity
 dose reduction would increase risk of relapse
 supportive care

17. References
Ahmed, M., Sternberg, A., Hall, G., Thomas, A., Smith, O., O’Marcaigh, A., Wynn, R., Stevens, R., Addison, M.,
King, D., Stewart, B., Gibson, B., Roberts, I., Vyas, P. (2004). Natural History of GATA1 mutations in Down
syndrome, Blood, 103(7):2480-2489.
Hitzler, J.K., Cheung, J., Li, Y., Scherer, S.W., Zipursky, A. (2003). GATA1 mutations in transient leukaemia and
acute megakaryoblastic leukaemia of Down syndrome, Blood, 101(11):4301-4304.
Hitzler, J.K., Zipursky, A. (2005). Origins of leukaemia in children with down syndrome, Cancer, 5:11-20.
Puumala, S.E., Ross, J.A., Olshan, A.F., Robison, L.L., Smith, F.O., Spector, L.G. (2007). Reproductive history,
infertility treatment, and the risk of acute leukaemia in children with down syndrome, Cancer, [Epub ahead of
print].
Shivdasani, R.A., Fujiwara, Y., McDevitt, M.A., Orkin, S.H. (1997). A loneage-selective knockout establishes the
critical role of transcription factor GATA-1 in megakaryocyte growth and platelet development, Embo J., 16:3965-
3973.
Slordahl, S.H. et al. (1993). Leukaemic blasts with markers of four cell lineages in Down's syndrome
(‘megakaryoblastic leukaemia’), Med. Pediatr. Oncol., 21:254-258.
Vyas, P., Crispino, J.D. (2007). Molecular insights into Down syndrome-associated leukemia, Current Opinion in
Pediatrics, 19:9-14.
Webb, D., Roberts, I., Vyas, P. (2007). Haematology of Down syndrome, Arch. Dis. Child. Fetal Neonatal Ed.,
[published online 5 Sep 2007].
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