Leukaemia in Down’s Syndrome

Overview

• Down’s Syndrome

• Leukaemia

• The link between Down’s Syndrome and Leukaemia

• Epidemiology

• Aetiology

• Future research

• Implications for other leukaemias

• Treatment

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

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

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

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

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

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

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

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

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

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

2) mutation of GATA1

expression of shortened

GATA1 (GATA1s)

3) extra, as of yet unknown event

not all cases of Transient

Leukaemia progress to AMKL

Picture: Hitzler & Zipursky, 2005

Aetiology

Transient Leukaemia with clinical signs of disease

?Transient Leukaemia with no clinical signs of disease

Picture: Ahmed et al, 2004

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’?

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.

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

ReferencesAhmed, 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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