- Letter to the Editor
- Open Access
Leukemic transformation driven by an ASXL1 mutation after a JAK2V617F-positive primary myelofibrosis: clonal evolution and hierarchy revealed by next-generation sequencing
© Ferrer-Marín et al.; licensee BioMed Central Ltd. 2013
Received: 1 September 2013
Accepted: 3 September 2013
Published: 8 September 2013
We have characterized the molecular changes underlying the transformation of a JAK2V617F+-myelofibrosis with trisomy 8, into a JAK2V617F-negative leukemia. Leukemic clone did not carry JAK2V617F mutation, but showed ASXL1 mutation (R693X). This mutation was identified in a low percentage at diagnosis by next-generation sequencing. Using this technology in serial specimens during the follow-up, we observed a progressive expansion of the ASXL1-mutated minor clone, whereas the JAK2V617F+-clone carrying trisomy 8 decreased. Hematologic progression occurred simultaneously with an ASXL1-R693X-negative lung-cancer. This is the first report showing a clear association between the expansion of an ASXL1-mutated clone and the leukemic transformation of myelofibrosis.
Letters to the editor
It is known that patients with JAK2V617F + myeloproliferative neoplasms (MPNs) can progress to a JAK2V617F¯ acute myeloid leukemia (AML)[1–3]. These two phases of the disease may represent two different clones, however, the time-dependent clonal hierarchy is just beginning to be elucidated[4, 5].
ASXL1 is the second most frequently mutated gene after JAK2 (~34.5%) in myelofibrosis (MF). ASXL1 mutations are also found in solid neoplasms and all types of myeloid malignancies. They are associated with aggressive disease but their role in leukemic transformation remains controversial. ASXL1 mutations correlated with progression to blast-state in myelodysplastic syndromes and chronic myelomonocytic leukaemia[9, 10] while in MF, they are detectable in most patients at diagnosis, and they are present in chronic- and blast-phases with the same prevalence. These findings suggest that ASXL1 mutations play a crucial role in the pathogenesis of MF[6, 11] but they do not directly cause a leukemic phenotype[2, 6]. We here characterize the molecular changes associated to the leukemic transformation of a patient with primary-MF (PMF) using next-generation sequencing (NGS). By the time of the hematologic progression, the patient also developed a lung adenocarcinoma. The relationship between the clonal hierarchy and phenotype disease over time are discussed.
Since ASXL1 has been involved in epithelial malignancy tumorigenesis and cancer, we sequenced ASXL1 gene in the hepatic metastatic tissue of lung cancer, but ASXL1-R693X mutation was not detected (Figure 2C), suggesting that at least three malignant clones might be present.
Overall, in this patient, at early disease, the PMF phenotype was driven mainly by a JAK2V617F + -dominant clone carrying trisomy 8. During the evolution this clone declined, whereas the ASXL1-mutated minor clone expanded, promoting the progression to leukemia. The reasons for these gradual shifts are unknown. Although hydroxyurea may induce a decrease in JAK2V617F allele burden in JAK2V617F + -MPNs[13, 19], leukemic transformation in MF can occur without any prior therapy. Furthermore, ASXL1-R693X mutation, as other mutations affecting genes with epigenetic role, likely favor the occurrence of secondary genetic events and, in association with other cooperating mutations, promotes blast-crisis.
The molecular mechanisms undergoing the myeloid leukemogenesis promoted by ASXL1 have been recently reported, but in MF, the role of ASXL1 mutations in leukemic transformation is still unclear[2, 6, 22]. By using NGS, we report, for the first time, an association between expansion of an ASXL1-mutated clone and MF progression to AML suggesting that in MF, as in other myeloid malignancies, ASXL1 mutations play a role in leukemic transformation. Given the prevalence of ASXL1 mutations in patients with MF, determination of ASXL1 mutation status in these patients could help in the molecular disease monitoring.
Written informed consent was obtained from the next of kin of the patient for publication of this Case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
We thank Dr J Corral for his helpful discussions.
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