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Mutations in ASXL1 are associated with poor prognosis across the spectrum of malignant myeloid diseases


The ASXL1 gene is one of the most frequently mutated genes in malignant myeloid diseases. The ASXL1 protein belongs to protein complexes involved in the epigenetic regulation of gene expression. ASXL1 mutations are found in myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML). They are generally associated with signs of aggressiveness and poor clinical outcome. Because of this, a systematic determination of ASXL1 mutational status in myeloid malignancies should help in prognosis assessment.

Mutations in the ASXL1 (additional sex combs like 1) gene were first reported in 2009 in myelodysplastic syndromes [1]. ASXL1 maps to chromosome region 20q11, close to the DNMT3B gene, and belongs to a family of three paralogs. ASXL1 comprises 12 exons and is expressed in most hematopoietic cell types.

Function of the ASXL1 protein

ASXL1 codes for a nuclear protein of 1084 residues characterized by an N-terminal helix-turn-helix domain, HARE-HTH [2], and an unusual C-terminal plant homeodomain (PHD), which may bind methylated lysines (Figure 1). The central part of ASXL1 contains an ASXH globular domain that may interact with a polycomb-associated deubiquitinase (DUB) [2, 3]. ASXL1 regulates epigenetic marks and transcription through interaction with polycomb complex proteins and various transcription activators and repressors [35]. In Drosophila, ASX forms a complex with the ubiquitin carboxy-terminal hydrolase calypso to constitute the recently identified polycomb repressive deubiquitinase (PR-DUB) complex [3, 6]. Human wild-type ASXL1 associates with the calypso ortholog BAP1 [7]. The calypso/BAP1 DUB deubiquitylates K119ub on histone H2A, leading to gene repression. However, the role of ASXL1 in leukemogenesis does not seem to be mediated by the DUB complex [7]. Recent data have shown that ASXL1 interacts with components of the polycomb complex PRC2, namely EZH2 and SUZ12, two proteins involved in the deposition of H3K27me3 histone repressive marks. These two PRC2 components are also mutated in myeloid malignant diseases [811]. Inhibition of ASXL1 function leads to loss of H3K27me3 histone marks. ASXL1 role could be to recruit the PRC2 complex to known leukemogenic loci such as HOXA genes [7]. ASXL1 also associates with HP1α/CBX5, a component of the heterochromatin repressive complex [6, 12]. HP1α binds to histone H3. JAK2 phosphorylates histone H3 and excludes HP1α from chromatin [13]. Thus, a potential functional link may exist between ASXL1 and JAK2 mutations but this remains to be demonstrated.

Figure 1
figure 1

Distribution of ASXL1 mutations along the protein. From top to bottom are shown the localization of the ASXL1 gene on chromosome region 20q11, the exon structure of ASXL1, and the ASXL1 protein with its conserved motifs and binding regions: HARE helix-turn-helix at the N-terminus, HP1/CBX5 binding region, ASXH, an α-helical domain that contains LXXLL (nuclear receptor boxes), and the C-terminal plant homeodomain (PHD) finger. Below reported mutations (see Table 1) are shown along the protein: circles and triangles indicate frameshift and nonsense mutations, respectively, and the colors correspond to the exon location.

The functions of the other ASXL proteins are poorly defined. ASXL2 has been shown to regulate heart [14] and bone development, as well as adipogenesis. Mouse ASXL2 has been identified as a regulator of bone mineral density and osteoclastogenesis [15] and whereas ASXL1 represses, ASXL2 increases the expression of adipogenic genes [16]. ASXL3 expression and functions remain to be determined [17].

ASXL1 and concomitant mutations in myeloid malignancies

The vast majority of the ASXL1 mutations found in myeloid malignancies affect the twelfth exon of the gene although rare mutations in other exons have been detected [18]. ASXL1 mutations are frameshift and nonsense mutations that are supposed to result in C-terminal truncation of the protein upstream of the PHD finger (Figure 1). The functional relevance of some reported missense mutations is not clear. The most frequent mutation, which accounts for more than 50% of all ASXL1 mutations, is a duplication of a guanine nucleotide (c.1934dupG); it leads to a frameshift (p.Gly646TrpfsX12). One study has described this mutation as a PCR artefact [19], but because it is not found in germ-line DNAs, control DNAs or other studied types of cancers such as breast cancer, it is now generally considered to be a bona fide mutation.

ASXL1 mutations are usually heterozygous, suggesting that haplo-insufficiency is the key pathological factor; however, the truncated ASXL1 protein could also have a dominant negative role in titrating out an interacting protein. Actually, recent data have demonstrated a loss of ASXL1 protein in leukemia samples with ASXL1 mutation, indicating that these mutations are loss-of-function disease alleles [7].

ASXL1 is mutated in all types of malignant myeloid diseases, including myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML). According to the series studied, ASXL1 mutation frequency varies from a few percent to more than 50% of cases (Table 1). ASXL1 mutations are most frequent in CMML (~ 45%). In MPNs, they are frequent in primary myelofibrosis (PMF)(34.5%) and rare in polycythemia vera (PV) or essential thrombocythemia (ET). In AML, they are found in secondary (30%) rather than in de novo cases (6.5%), and in AML with normal karyotype ASXL1 mutations are mutually exclusive with NPM1 mutations [20]. ASXL1 is the second most frequently mutated gene in MDSs after TET2[21]. In MDSs, ASXL1 mutations are more frequent in refractory anemia with excess of blasts (RAEB) than in the other forms such as refractory anemia with ring sideroblasts (RARS) [1, 5, 22]. ASXL1 mutations are further detected in rare cases of juvenile myelomonocytic leukemia (JMML) [23] and in RARS-T [24].

Table 1 Mutations in ASXL1 gene in published studies

With the exception of NPM1 and FLT3, it seems that ASXL1 mutations coincide with mutations in many known genes including EZH2[18], IDH1/2, RUNX1 and TET2[21, 22]. Although ASXL1 functions are related to the PRC2 complex, which includes EZH2, ASXL1 and EZH2 mutations are not mutually exclusive [18, 38]. ASXL1 mutations can also cooperate with mutations in genes encoding signaling (CBL, JAK2, NF1, RAS) and splicing proteins (SF3B1, SRSF2, U2AF35). For example, in MDSs, ASXL1 mutations are more frequent in U2AF35-mutated patients than in U2AF35 wild-type patients [39]. In MPNs, ASXL1 mutations are found with the same frequency in JAK2V617F and JAK2 wild-type cases [26, 36]. In MDSs, ASXL1 mutations are often associated with RUNX1 mutations, and, in AMLs, with RUNX1 and CEBPA. [29, 33, 40].

Other alterations in ASXL1, ASXL2 and ASXL3

Few deletions of the gene have been reported and ASXL1 is generally not included in the more telomeric 20q13 deletion that is often observed in myeloid diseases. The ASXL1 gene can be translocated and fused to the PAX5 gene in acute lymphoblastoid leukemia [41] and altered by germ-line mutations in the Bohring-Opitz syndrome; this severe syndrome leads to death at an early age preventing to know whether susceptibility to hematopoietic diseases might result from ASXL1 germ-line mutations [42]. In recent genome sequencing studies rare mutations in ASXL1 and ASXL3 have also been found in chronic lymphocytic leukemia [43] but not in T-cell acute leukemia [44]. Mutations in ASXL2 and ASXL3 have not been found in myeloid diseases so far, but ASXL2-MYST3 and EPC1-ASXL2 fusions have been identified in myelodysplastic syndrome and T-cell acute leukemia, respectively [45, 46]. Both MYST3 and EPC1 are epigenetic regulators and these fusion proteins probably disrupt epigenetic protein complexes.

Animal models of ASXL1 loss

In a first model of Asxl1 gene knock-out in the mouse ASXL1 loss mildly perturbed myelopoiesis but did not trigger an actual hematological malignancy [47]. However, the effect of the absence of ASXL1 protein may have been masked by partially penetrant perinatal lethality. In another, more recent model of conditional Asxl1 gene knock-out, the animals developed a strong hematopoietic phenotype consistent with an MDS with myeloproliferative features. In cooperation with NRAS oncogenic mutation the absence of ASXL1 triggered an MDS/MPN. These observations were confirmed by experiments in hematopoietic cells using shRNA directed against ASXL1, which were highly coherent with the expected role of ASXL1 in leukemogenesis [7].

ASXL1 mutations in disease evolution

Like TET2 mutations, ASXL1 mutations are found in chronic and acute stages of myeloid malignancies. In a study of MPNs, with the exception of a single patient who acquired both ASXL1 and TET2 mutations, all patients with ASXL1 mutation at leukemic transformation already had ASXL1 mutation at the chronic stage [25]. In a series of secondary AML with multilineage dysplasia we found that in cases resulting from a transformation of a known MDS the same ASXL1 mutation was present at both the chronic and acute stages (Devillier et al., submitted). These observations suggest that ASXL1 mutations may constitute early hits in leukemogenesis and precede other alterations such as JAK2 and TET2 mutations [24, 25, 28]. However, there is also evidence to suggest that the opposite is true in some cases. In MPNs, for example, the proportion of ASXL1 mutations is higher in post-PV myelofibrosis (MF) and post-ET MF than in PV and ET. This suggests that the ASXL1 mutation may follow a JAK2 mutation and could therefore help predict the risk of evolution from PV and ET to MF [26, 36, 48]. As such, ASXL1 mutations may play a crucial role in the pathogenesis of PMF, as well as in the molecular progression from the chronic phase of a previous PV or ET to MF. Finally, in MDSs and CMML, ASXL1 mutations seem to be present in chronic phases and precede transformation and in rare cases, ASXL1 mutations can be lost or acquired during relapse of de novo AML [29].

ASXL1 mutations in disease outcome

A number of studies have linked ASXL1 mutations to the outcome of malignant myeloid diseases. In a study of MPNs based on the DIPSS-plus score [49] (Dynamic International Prognostic Scoring System for primary myelofibrosis), ASXL1 mutation tended to be associated with an aggressive disease and a poor overall survival [26]. In a large study of PMF patients ASXL1 mutations were associated with shorter overall survival [50]. In CMML, the presence of an ASXL1 mutation could help predict transformation to AML [30]. In MDSs, ASXL1 mutations are associated with a reduced time to progression in AML and constitute an independent prognostic marker [37]. Finally, a study of 18 genes in a large cohort of MDSs showed that mutations in 5 genes had prognostic impact: TP53, EZH2, ETV6, RUNX1 and ASXL1[21]. Coupled with the standardized international prognostic scoring system (IPSS), mutations in these five genes could help refine the prognosis evaluation of MDSs.

By contrast, a study of a large cohort of 605 AML cases without cytogenetic prognostic markers other than 11q23 abnormalities, reported that ASXL1 mutations were not associated with outcome [35]. However, they were associated with shorter overall survival in patients with intermediate-risk AML [29, 33]. A recent study of 476 cases with intermediate-risk de novo AML showed that ASXL1 mutations have a major impact on outcome [51]. According to the current European LeukemiaNet (ELN) guidelines for the diagnosis and management of AML, AMLs with normal karyotype are classified into two genetic categories based on their NPM1, FLT3-ITD and CEBPA mutation status: the ELN Favorable category is defined as mutated CEBPA and/or mutated NPM1 without FLT3-IT; all remaining cases (ie, those with wild-type CEBPA, and wild-type NPM1 with or without FLT3-ITD or mutated NPM1 with FLT3-ITD) form the ELN Intermediate-I category [52, 53]. ASXL1 mutations have been associated with inferior survival among ELN Favorable, but not among ELN Intermediate-I patients [40]. Taken together, these data show that ASXL1 mutations have prognostic value in certain subgroups of AML patients.


In almost all studies, and whatever the type of myeloid malignancy, ASXL1 mutations are associated with adverse features including, but not limited to myelodysplasia, myelofibrosis or progression to AML. Systematic detection of ASXL1 mutations could thus help in the assessment of disease and should perhaps be implemented in routine practice, whether associated with already systematically-surveyed mutations (CEBPA, JAK2, FLT3, NPM1) or in upcoming systematic genome analyses.


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Our work in this field is supported by Inserm, Institut Paoli-Calmettes and grants from the Association pour la Recherche sur le Cancer (DB) and Association Laurette Fugain (MJM 2010).

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Gelsi-Boyer, V., Brecqueville, M., Devillier, R. et al. Mutations in ASXL1 are associated with poor prognosis across the spectrum of malignant myeloid diseases. J Hematol Oncol 5, 12 (2012).

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  • ASXL1
  • Gene mutations
  • Myeloid diseases