1: Cancer Res. 2005 Oct 15;65(20):9152-4. 

Association between acquired uniparental disomy and homozygous gene mutation in
acute myeloid leukemias.

Fitzgibbon J, Smith LL, Raghavan M, Smith ML, Debernardi S, Skoulakis S,
Lillington D, Lister TA, Young BD.

Cancer Research UK Medical Oncology Laboratory, Barts and the Royal London
School of Medicine, Queen Mary College, London, United Kingdom.

Genome-wide single nucleotide polymorphism analysis has revealed large-scale
cryptic regions of acquired homozygosity in the form of segmental uniparental
disomy in approximately 20% of acute myeloid leukemias. We have investigated
whether such regions, which are the consequence of mitotic recombination,
contain homozygous mutations in genes known to be mutational targets in
leukemia. In 7 of 13 cases with uniparental disomy, we identified concurrent
homozygous mutations at four distinct loci (WT1, FLT3, CEBPA, and RUNX1). This
implies that mutation precedes mitotic recombination which acts as a "second
hit" responsible for removal of the remaining wild-type allele, as has recently
been shown for the JAK2 gene in myeloproliferative disorders.

PMID: 16230371 [PubMed - in process]


---------------------------------------------------------------


2: Br J Haematol. 2005 Feb;128(3):318-23. 

Development of a human acute myeloid leukaemia screening panel and consequent
identification of novel gene mutation in FLT3 and CCND3.

Smith ML, Arch R, Smith LL, Bainton N, Neat M, Taylor C, Bonnet D, Cavenagh JD,
Andrew Lister T, Fitzgibbon J.

Cancer Research UK Medical Oncology Unit, Charterhouse Square, Barts and the
London School of Medicine and Dentistry, London. matt.lws@virgin.net

A study was undertaken to develop an acute myeloid leukaemia (AML) screening
panel to uncover novel recurring gene mutations. Analysis was performed on six
genes known to be mutated in AML (RUNX1, FLT3, KIT, CEBPA, PTPN11 and NRAS) and
an additional two candidate genes (CCND3 and FES) in a panel of 175 primary
human AML samples that included all French-American-British types except M3, and
all cytogenetic risk groups. One hundred and fifteen mutations were identified
in 97 (55%) patients comprising 81 patients (46%) with one mutation, 14 patients
(8%) with two mutations and two patients (1%) with three mutations. Fifty-five
of 88 (63%) patients with normal karyotype AML had at least one mutation.
Correlation was observed between KIT mutation and 'favourable risk' cytogenetics
(P <0.001), CEBPA mutation and 'intermediate risk' cytogenetics (P=0.045), and
PTPN11 mutation and 'poor risk' disease (P <0.001). The frequency of individual
gene mutation was in accordance with previously published studies. Three novel
mutations of FLT3 were detected (Y589D, D839G, Y842H) that would have been
overlooked by conventional gel electrophoresis. A 51-bp deletion was detected in
CCND3 in a patient with normal karyotype AML. This validated panel now provides
an important tool to evaluate other candidate genes in the genesis of myeloid
malignancy.

PMID: 15667533 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


3: Nat Med. 2001 Apr;7(4):444-51. 

Comment in:
    Nat Med. 2001 Apr;7(4):407-8.

AML1-ETO downregulates the granulocytic differentiation factor C/EBPalpha in
t(8;21) myeloid leukemia.

Pabst T, Mueller BU, Harakawa N, Schoch C, Haferlach T, Behre G, Hiddemann W,
Zhang DE, Tenen DG.

Hematology/Oncology Division, Harvard Institutes of Medicine, Harvard Medical
School, Boston, Massachusetts, USA.

The transcription factor CCAAT/enhancer binding protein alpha, or C/EBPalpha,
encoded by the CEBPA gene, is crucial for the differentiation of granulocytes.
Conditional expression of C/EBPalpha triggers neutrophilic differentiation, and
Cebpa knockout mice exhibit an early block in maturation. Dominant-negative
mutations of CEBPA have been found in some patients with acute myeloid leukemia
(AML), but not in AML with the t(8;21) translocation which gives rise to the
fusion gene RUNX1-CBF2T1 (also known as AML1-ETO) encoding the AML1-ETO fusion
protein. RUNX1-CBF2T1 positive-AML blasts had eight-fold lower CEBPA RNA levels
and undetectable C/EBPalpha protein levels compared with other subgroups of AML
patients. Conditional expression of RUNX1-CBF2T1 in U937 cells downregulated
CEBPA mRNA, protein and DNA binding activity. AML1-ETO appears to suppress
C/EBPalpha expression indirectly by inhibiting positive autoregulation of the
CEBPA promoter. Conditional expression of C/EBPalpha in AML1-ETO-positive
Kasumi-1 cells results in neutrophilic differentiation. We suggest that
restoring C/EBPalpha expression will have therapeutic implications in
RUNX1-CBF2T1-positive leukemias.

PMID: 11283671 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------