AML with t(7;21)(p22;q22):A new recurrent semi-cryptic

RUNX1 rearrangement

M. Sales1, N. Foster1, S. Tauro2, J. Cunningham1, N. Pratt1

Departments of Cytogenetics1 and Haematology2

Ninewells Hospital, Dundee

ACC Spring MeetingLiverpool 2008

Acute Myeloid Leukaemia (AML)

• WHO: Clonal expansion of myeloid blasts in bone marrow (BM), peripheral blood (PB) or other tissue

• More than 20% blasts in BM or PB

• Can be AML with less than 20% blasts if there is a recognised cytogenetic abnormality

e.g. t(8;21), t(15;17) etc

• Many other cytogenetic abnormalities reported (Karyotyping & FISH)

RAEB

• Myelodysplastic syndrome (MDS)• Refractory anaemia with excess blasts

Cytopenias (in PB) 5-9% blasts RAEB-1 10-19% blasts RAEB-2 Unilineage or multilineage dysplasia <1x109/l monocytes

• RAEB risk of evolution to AML (RAEB-2 = 33%)• RAEB-2 median survival 10 months• Some RAEB-2 are possibly early stage AML

Patient Information: Clinical

• 68 year old female • GP with fatigue & frequent nail bed infections• November 2007 diagnosed with RAEB-2 (17%

blasts) and erythroid & megakaryocytic dysplasia• Entered into the intensive arm of AML16 trial

Randomised to– DClo3+5 +Myelotarg (Daunorubicin/Clofarabine/Myelotarg) - 1st induction

– Cytogenetic remission

– DClo3+5 (Daunorubicin/Clofarabine) - 2nd induction

– DA2+5 (Daunorubicin/Cytarabine) - consolidation

– Azacytidine - maintenance

• December 2007 remission

Patient Information: Genetics

• Large number of tetraploid cells

• Small chromosome 21 investigated by FISH

• TEL/AML1 extra signal probe (Vysis)

• Normal TEL (ETV6) & split AML1(RUNX1) signals

• Reverse DAPI & WCP confirmed chromosome 7

• November 2007 Karyotype:

46,XX,t(7;21)(p22;q22)[12]/92,idemx2[21]/46,XX[17]

• December 2007 complete cytogenetic remission

Diploid Karyotype

46,XX,t(7;21)(p22;q22)

Tetraploid Karyotype

92,XXXX,t(7;21)(p22;q22)x2

TEL/AML1 extra signal probe diploid cell

der(7)

der(21)Normal 21

Reverse DAPI FISH image

TEL/AML1 extra signal probetetraploid cell

21

21der(21)

der(21)

der(7)

der(7)

Reverse DAPI FISH image

WCP7 & TEL/AML1 extra signal probediploid cell

der(7) der(21)

WCP7 & TEL/AML1 extra signal probe tetraploid cell

der(7)

der(7)

der(21)

der(21)

Ideograms

7 21 7 21

Hiller B, Bradtke J, Balz H and Rieder H (2004): "CyDAS Online Analysis Site", http://www.cydas.org/OnlineAnalysis/"

t(7;21)

Paulsson et al (2006): Patient info

• 7 yr old boy - Presented March 1995 Pyrexic tonsillitis & cervical adenitis Hypercellular BM Blasts difficult to classify morphologically Immunophenotyping = AML M0

• Treatment – initially by NOPHO-AML-93 protocol After induction still 25% blasts 3 additional chemotherapy blocks - CR Allogeneic stem cell transplant (sister) June 1995 Relapse March 2000 – abnormal cytogenetics 2nd CR April 2000 followed by donor lymphocyte infusions

• Patient still OK April 2005

Paulsson et al (2006): Genetics

• Apparently normal male at diagnosis

• Karyotype at relapse46,XY,t(4;6)(q24;p11),del(5)(q15),t(11;18)(q23;q21)[24]

• t(7;21)(p22;q22) found while screening paediatric leukaemia's for t(7;21)(q36;p13)

• Initially detected by WCP for chromosome 7

• LSI TEL/AML1 extra signal probe (Vysis)

• RUNX1 rearranged with USP42 (complex)

Paulsson et al (2006): Findings

• USP42 – protease in ubiquitin pathway

• Highly expressed in skeletal muscle, liver & pancreas and weakly in brain, placenta & heart.

• Also in normal BM and 1o AMLs

• Fusion protein is thought to have a dominant-negative effect on normal RUNX1 and may retain USP42 protease activity

Conclusion

• Lack of a visible cytogenetic abnormality does not preclude chimeric genes

• cryptic rearrangements previously reported in AML MLL/ARHGEF12 - del(11q) MLL/CBL - del(11q) Nup98/NSD1 - t(5;11)(q35;p15.5)

• Now add t(7;21) to list

• Others likely – MFISH/SKY & aCGH

• Larger study required to assess actual frequency and clinical implications (UKCCG coordinated)

AML with t(7;21)(p22;q22):A new recurrent semi-cryptic

RUNX1 rearrangement

M. Sales1, N. Foster1, S. Tauro2, J. Cunningham1, N. Pratt1

Departments of Cytogenetics1 and Haematology2

Ninewells Hospital, Dundee

ACC Spring MeetingLiverpool 2008