Concise Review

Leukemia (2012) 26, 2027–2031; doi:10.1038/leu.2012.86; published online 1 May 2012

Spliceosome and other novel mutations in chronic lymphocytic leukemia and myeloid malignancies

F Damm1,2,3, F Nguyen-Khac4,5, M Fontenay6,7,8,9 and O A Bernard1,2,3,6

  1. 1Institut Gustave Roussy, Villejuif, France
  2. 2INSERM, U985, Villejuif, France
  3. 3Université Paris Sud-11, Orsay, France
  4. 4Service d’Hématologie Biologique, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France
  5. 5INSERM U872; Université Pierre et Marie Curie-Paris 6, Paris, France
  6. 6Assistance Publique-Hôpitaux de Paris, Service d’Hématologie Biologique, Hôpital Broca-Cochin-Hôtel-Dieu, Paris, France
  7. 7Département d’Immunologie et Hématologie, Institut Cochin, Paris, France
  8. 8INSERM U1016, CNRS UMR8104, Paris, France
  9. 9Université Paris Descartes, Paris, France

Correspondence: Dr OA Bernard, Institut Gustave Roussy, 39 rue Camille Desmoulins, Villejuif 94805, France. E-mail:

Received 6 March 2012; Revised 16 March 2012; Accepted 19 March 2012
Accepted article preview online 9 April 2012; Advance online publication 1 May 2012



Spliceosome mutations represent a new generation of acquired genetic alterations that affect both myeloid and lymphoid malignancies. A substantial proportion of patients with myelodysplastic syndromes (MDSs) or chronic lymphocytic leukemia (CLL) harbor such mutations, which are often missense in type. Genotype–phenotype associations have been demonstrated for one of these mutations, SF3B1, with ring sideroblasts in MDS and 11q22 deletions in CLL. Spliceosome mutations might result in defective spliceosome assembly, deregulated global mRNA splicing, nuclear-cytoplasm export and altered expression of multiple genes. Such mutations are infrequent in other lymphomas, which instead display a separate group of novel mutations involving genes whose products are believed to affect histone acetylation and methylation and chromatin structure (for example, EZH2 and MLL2). On the other hand, some mutations (for example, NOTCH1) occur in both CLL and other immature and mature lymphoid malignancies. In the current review, we discuss potential mechanisms of cell transformation associated with spliceosome mutations, touch upon the increasing evidence regarding the clonal involvement of hematopoietic stem cells in some cases of otherwise mature lymphoid disorders and summarize recent information on recently described mutations in lymphomas.


CLL; MDS; mutations; spliceosome



In a series of recently published work, the coding sequences of the DNA obtained from mononuclear cells of the bone marrow of patients with myelodysplastic syndromes (MDSs) were compared with presumably germline DNA (T lymphocytes or buccal swab).1, 2, 3 The results have included identification of approximately 10 acquired mutations per patient sample and confirmation of the frequency of previously recognized mutations.1 More importantly, the particular studies revealed the existence of mutations in genes whose products are involved in controlling the mechanism of splicing of pre-messenger RNA. Such mutations were mutually exclusive and were detected in 45–85% of patients with MDS;1 the majority constituted missense mutations located in restricted regions of proteins.

A similar analysis was conducted in chronic lymphocytic leukemia (CLL) where DNA from tumor cells (CD19+ and CD5+ lymphocytes) was compared with that of non-tumor cells (granulocytes or fibroblasts).4, 5, 6, 7 In addition to genes already known to be mutated in this disease, such as TP53 and ATM, 11 genes were found to be recurrently affected.4, 6 The pathway analyses predicted that these mutations affected DNA damage repair and cell cycle, the Wnt, NOTCH1 and inflammatory/TLR signaling pathways, and, as was the case in MDS, control of splicing mechanisms.4

The common novel observation, from the above-mentioned studies, in both MDS and CLL, was the identification of mutations in genes whose products are involved in the control of RNA splicing.8 The involvement of oncogenes in RNA processing has long been known;9 OTT (aka RBM15), fused to MAL (aka MKL1) by t(1;22)(p13;q13) in acute megakaryoblastic leukemia, is involved in the export of mRNA to the cytoplasm,10, 11, 12, 13 whereas other gene rearrangements resulting in fusion proteins have been shown to involve nucleopore proteins such as NUP98 and NUP214.14, 15, 16, 17 Until now, however, the involvement of abnormalities in RNA metabolism in cellular transformation has remained elusive.


SF3B1 mutations

The SF3B1 gene, which encodes a protein involved in RNA splicing, is mutated in 10–15% of patients with MDS and in a similar proportion of those with CLL (Table 1). The identification of a gene mutated in both MDS and CLL was unexpected because MDS is considered as a stem cell-derived clonal disorder, whereas CLL was believed to originate from cells committed to B-lymphoid differentiation. It is possible that SF3B1 mutations have similar pathogenetic consequences in both CLL and MDS by participating in the transformation of a B-cell and a myeloid progenitor, respectively. The occurrence of SF3B1 mutations in other hematological malignancies, such as myeloproliferative neoplasms, and solid tumors supports the generic pathogenetic relevance of SF3B1 mutations. Sf3b1-knockout mice exhibit a homeotic phenotype that has been suggested to be linked to Polycomb repressive complex activity.18

In line with the above observations, it was recently demonstrated that hematopoietic stem/progenitor cells from patients with CLL were capable of generating clonal B cells with a CLL-like phenotype, thus implicating hematopoietic stem/progenitor cells in the pathogenesis of CLL, a mature lymphoid malignancy.19 Similarly, TET2 mutations are found in both myeloid and lymphoid malignancies and in both instances, the mutations may be present in myeloid progenitors, again suggesting a stem cell origin for some mature lymphoid malignancies.20 A similar scenario involving DNMT3A mutations was recently communicated.21

In both MDS and CLL, SF3B1 mutations have been correlated with certain disease phenotype and a prognostic relevance has been suggested but not validated. In MDS, SF3B1 mutations cluster with the presence of ring sideroblasts3 and might be associated with better prognosis, although other investigators have questioned the histopathology-independent prognostic effect of the mutation in MDS.22, 23, 24, 25 In CLL, SF3B1 mutations were associated with deletions of chromosomal region 11q22 and ATM mutations (ATM is located at chromosome 11q22), as well as poor prognosis and resistance to fludarabine therapy.4, 6, 26


Other spliceosome mutations

In MDS, eight genes encoding proteins involved in RNA splicing are mutated with a variable frequency.1, 2, 3 In addition to SF3B1, U2AF35 and SRSF2 are among the most frequently mutated in MDS and may be associated with prognosis and phenotype.27, 28, 29 SRSF2 is also frequently mutated in leukemic transformation of myeloproliferative neoplasm.30 These proteins are part of ribonucleoprotein complexes called spliceosomes and are involved in the splicing of introns during pre-mRNA maturation. They belong to the E/A complexes involved in the recognition of pre-mRNA during the very first steps of splicing, more precisely to the recognition of the polypyrimidine track and the acceptor splice site and also the exon splice enhancer.31 With the exception of ZRSR2, which is located on the X chromosome and is affected by inactivating mutations, the other spliceosome mutations are mostly regional missense mutations, often recurrently targeting a single amino acid. This type of mutational profile often indicates a gain of function and could possibly alter spliceosome-assembly efficiency or the splicing steps themselves. As a result, the expression of many genes could be affected because of intron presence in the mature transcript, the omission of exons or the deregulation of alternative splicing. The role of alternative splicing in cell differentiation has been well established and deregulation of these processes could be involved in cell transformation.32, 33


Potential consequences of spliceosome mutations

Splicing is often tightly coupled with transcription34, 35 and recent work suggests that alternative splicing might be affected by chromatin structure and histone modification.35, 36 Some of these effects might involve direct recruitment of splice factors by chromatin mark readers, as has been shown for MRG15 (also known as MORF4L1) binding to H3K36me3 and recruitment of the polypyrimidine tract-binding protein to the nascent mRNA.37 The lack of SF3B1 may impair PRC1 function18 and the SPT3-TAFII31-GCN5L acetylase complex may also interact with splice factors.38 Mutations affecting ‘splice genes’ may therefore alter either upstream the efficiency of transcription or downstream the kinetics of mRNA export to the cytoplasm and/or lead to RNA degradation.39 It is conceivable that the rates of transcription, splicing and transport to the cytoplasm are linked and influence chromatin structure. Accordingly, a slowdown (or acceleration) of these processes may lead to closing (or opening) of the chromatin, and thus to abnormal cell differentiation.

Changes affecting other aspects of the biology of RNA than the early phases of splicing are also likely to have a role in the transformation process. In CLL, mutations of CPSF2, DDX3X and XPO1 have been observed.4 The product of CPSF2 is involved in the process of polyadenylation of messenger RNA;40 DDX3X is a member of the DEAD-box RNA helicase family which is involved in many steps of RNA metabolism;41, 42 XPO1 (aka CRM1) participates to the nucleo-cytoplasmic export of proteins and RNA.43 Mutations in genes whose products are involved in translational control or mRNA stability have been also described in myeloma, another type of tumor of the B-lymphoid lineage.44 Mutations, which appear to be inactivating mutations and associated with the loss of the wild-type copy of the gene, have been described in DIS3, which encodes the catalytic subunit of the exosome involved in RNA maturation and turnover.45 Mutations in the exoribonuclease DIS3 could lead to an accumulation of certain non-coding RNAs and interfere with transcription as exemplified for XRN1/SEP1 exoribonuclease gene in yeast.46 Of note, DIS3 mutations are also observed in acute myeloid leukemia47 and in some patients with CLL.4 Mutations in the LRRK2 gene have also been reported. Among several functions, LRRK2 protein is involved in the control of translation by its ability to phosphorylate the translation factor 4EBP,48 have also been reported in myeloma. In addition, the FAM46C gene, product of which is predicted to have a role in translation or RNA stability, is also mutated in 13% of myeloma.44

It is intriguing that several steps of the biology of RNA maturation, transport, translation and degradation appear to be targeted in the processes of malignant transformation (Figure 1). In aggregate, these observations add to the description on the role of the loss of the ribosomal protein gene RPS14 in the pathogenesis of the dyserythropoiesis in MDS associated with 5q−49 and also the emerging role of non-coding RNA in the regulation of splicing.36 The potential value of these mutations as a drug target is currently being explored.50

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact or the author

Schematic representation of RNA biology. Examples of genes whose products are predicted to be involved in RNA biology and found mutated in hematological malignant disorders, including AML, MDS, CLL and myeloma. RNA degradation also occurs in the nucleus.

Full figure and legend (89K)


Other novel mutations in lymphomas

Some cases of CLL (and possibly others with myeloma) might be closer to MDS in their clonal structure than they are to other mature B-cell malignancies. Unlike the case with CLL, splice gene mutations have yet to be described in B-cell lymphomas,6, 51, 52 whereas several chromatin-modifier genes are targeted by mutation in B lymphomas. Mutation of Y641 of the H3K27 methylase EZH2 is observed in diffuse large B-cell lymphoma (21%) and follicular lymphoma (7%).53 Mutant EZH2 result in a decrease in monomethylation and an increase in trimethylation activity relative to the wild-type enzyme.54, 55

The MLL2 gene codes for an H3K4 methylase (H3K4me3 is associated with active chromatin) and is inactivated in B-cell NHL (up to 20–30% of diffuse large B-cell lymphoma and 90% of follicular lymphoma).51, 52 The related MLL, MLL3 and MLL5 genes may also be lost by genomic deletion. Inactivation of KDM2B, a H3K4 and K36 demethylase, of CBP and P300, two well-known and related histone and non-histone acetyltransferases,56 are also observed (~40% of follicular lymphoma and diffuse large B-cell lymphoma for CBP and P300). As proposed, activation of EZH2 and inactivation of CBP/P300 may similarly enhance gene-silencing through H3K36 trimethylation.52, 57 Mutations of MEF2B, encoding a Ca++ responsive transcription factor known to recruit CBP and P300 to DNA, are also observed (13% of follicular lymphoma and diffuse large B-cell lymphoma), which may point to genes important in this process. In another lymphoma subtype, primary mediastinal B-cell lymphoma, amplification of the 9p24 region, which include JAK2 and JMJD2C, is thought to increase gene expression by preventing the recruitment of HP1α through H3Y41 phosphorylation.58

From those data, molecular mechanisms driving B lymphoma appear to be different than those implicated in CLL. However, there are some common mutations.59 Mutations involving NOTCH1 are well described in T-cell acute lymphoblastic leukemia and result in constitutive activation of the transcription of the NOTCH pathway target genes.60 During maturation, the NOTCH1 protein is cleaved into an extracellular domain and an intracellular portion that interact with each other. The interaction of the NOTCH1 receptor with its ligands releases intracellular portion, which translocates into the nucleus where it interacts with the transcription factor RBPJK and results in transcriptional activation of target genes.

In T-cell acute lymphoblastic leukemia, mutations of NOTCH1 can, depending on their location, either facilitate the dissociation of intracellular portion or cause the loss of a protein-destabilizing domain (PEST) in intracellular portion. This latter type of mutations are found in CLL, especially as a frameshift mutation affecting the codon for amino-acid P2515.4, 7, 61 Comparable NOTCH1 mutations are also found in B-cell lymphomas62 and both activation and inactivation of the pathway have been identified in hematopoietic and non-hematopoietic diseases.63 As with T-cell acute lymphoblastic leukemia, mutations inactivating the FBXW7 gene, which codes normal feedback control of Notch signaling (which also control CMYC stability64), are also observed in CLL. In some series, mutations of NOTCH1 and FBXW7 are associated with the presence of trisomy 12 and the non-mutated status of the hypervariable regions of immunoglobulin genes.65, 66, 67, 68

MYD88 is mutated in CLL, the most frequent mutations being L265P mutation, as in B-cell lymphoma.69 MYD88 missense mutations are activator type mutations that result in the constitutive activation of the transcription factors STAT3 and NFκB. It is one of the many ways to activate NFκB and other prosurvival and proliferative signaling in B-cell lymphoma.70 In CLL, MYD88 mutations are associated with the mutated immunoglobulin gene status and deletions of chromosomal region 13q14.4, 5


Concluding remarks

The cellular consequences of mutations targeting ‘splice genes’ appear to be detrimental to cell growth.1 Understanding the mechanisms of action of these mutations is essential for the development of targeted therapies, but will require further functional analysis and development of sophisticated models. Those experiments, together with more clinical studies, will determine the respective contribution of these oncogenic events to cellular transformation, identify rational targets for drug development and potentially lead to more accurate molecular classification systems.



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Work in the authors’ laboratories was supported by the INSERM, Direction de la recherche clinique AP-HP (PHRC MDS-04), INCa, association Laurette Fugain and labellisation from Ligue Nationale Contre le Cancer. Frederik Damm is supported by a grant from the Deutsche Krebshilfe. We want to thank William Vainchenker, Daniel Birnbaum and Christian Bastard for their helpful discussion.