High-density single nucleotide polymorphism array analysis and ASXL1 gene mutation screening in chronic myeloid leukemia during disease progression

Abstract

We have undertaken a genome-wide single nucleotide polymorphism (SNP) array analysis of 41 chronic myeloid leukemia (CML) patients. In total, 44 regions of uniparental disomy (UPD) 43 Mb were identified in 24 of 32 patients in chronic phase (CP), and 21 regions of UPD 43 Mb were identified in 13 of 21 patients in blast crisis (BC). Chromosome 8 had the highest frequency of UPD regions in both CP and BC samples. Eight recurrent regions of UPD were observed among the 41 patients, with chromosome 8 showing the highest frequency. Ten regions of copy number change (CNC) 43 Mb were observed in 4 of 21 patients in BC, whereas none were observed in CP. We have identified several recurrent regions of UPD and CNC in CML that may be of pathogenetic importance. Overrepresentation of genomic aberrations (UPD and copy number gain) mapping to chromosome 8 was observed. Selected candidate genes mapping within the aberrant genomic regions were sequenced and mutation of the TP53 gene was observed in one case in BC and of the ASXL1 gene in 6 of 41 cases in CP or BC. Mutation of ASXL1 represents an important new molecular abnormality in CML.

Acquired ASXL1 mutations are common in patients with inherited GATA2 mutations and correlate with myeloid transformation

“…These two mutations have been reported at similar rates in previous studies of AML and CMML. 10,11,[17][18][19][20][21] The remaining six mutations were found once each. Three of them were previously unreported: G652S, L817fs*1, and L866X.…”

Loss of Asxl1 leads to myelodysplastic syndrome–like disease in mice

“…[1][2][3][4][5] Recently, copious clinical studies showed that ASXL1 is altered in multiple forms of myeloid malignancies, including myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), MDS/MPN (such as chronic myelomonocytic leukemia [CMML] and juvenile myelomonocytic leukemia [JMML]), and acute myeloid leukemia (AML). [6][7][8][9][10][11][12] Alterations in ASXL1 are generally associated with signs of aggressiveness and poor prognosis in patients with CMML, MDS, myelofibrosis, and AML. [13][14][15][16][17] ASXL1 alterations in myeloid malignancies have been reported as mutations and/or deletion, with the majority being frameshift and nonsense mutations, [6][7][8][9][10][11][12] resulting in C-terminal truncation of the protein upstream of the PHD finger.…”

“…[6][7][8][9][10][11][12] Alterations in ASXL1 are generally associated with signs of aggressiveness and poor prognosis in patients with CMML, MDS, myelofibrosis, and AML. [13][14][15][16][17] ASXL1 alterations in myeloid malignancies have been reported as mutations and/or deletion, with the majority being frameshift and nonsense mutations, [6][7][8][9][10][11][12] resulting in C-terminal truncation of the protein upstream of the PHD finger. A recent study showed that truncated forms of the ASXL1 protein were undetectable in leukemia samples with ASXL1 mutations, suggesting that these mutations are likely "bona fide loss-of-function" disease alleles.…”

Mutation analysis of TET2, IDH1, IDH2 and ASXL1 in chronic myeloid leukemia

“…All other sequence variations have already been described as SNPs (data not shown). Recently, Boultwood et al 8 have reported ASXL1 mutations in 6 of 41 (14.6%) patients from both CP and blast crisis CML. In our study, ASXL1 alterations (8.8%) were not detected when patients reached molecular response, and were not necessarily found at relapse.…”