1. 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 Meeting
Liverpool 2008

2. 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)

3. 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

4. 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) nd induction
DA2+5 (Daunorubicin/Cytarabine) consolidation
Azacytidine maintenance
December 2007 remission

5. 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

6. Diploid Karyotype
46,XX,t(7;21)(p22;q22)

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

8. TEL/AML1 extra signal probe diploid cell
der(21)
Normal 21
der(7)
Reverse DAPI FISH image

9. TEL/AML1 extra signal probe tetraploid cell21
der(21) 21
der(7)
der(21)
der(7)
Reverse DAPI FISH image

10. WCP7 & TEL/AML1 extra signal probe diploid cell
der(7)
der(21)

11. WCP7 & TEL/AML1 extra signal probe tetraploid cell
der(7)
der(21)
der(21)
der(7)

12. Ideograms
t(7;21) 7 7 21 21
Hiller B, Bradtke J, Balz H and Rieder H (2004): "CyDAS Online Analysis Site",

13. 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

14. Paulsson et al (2006): Genetics
Apparently normal male at diagnosis
Karyotype at relapse
46,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)

15. 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

16. 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)

17. 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 Meeting
Liverpool 2008