Myelodysplasias

Age, JAK2V617F and SF3B1 mutations are the main predicting factors for survival in refractory anaemia with ring sideroblasts and marked thrombocytosis

Article metrics

Abstract

Refractory anaemia with ring sideroblasts (RARS) and marked thrombocytosis (RARS-T) is a provisional entity in the World Health Organisation 2008 classification and has previously been shown to have a high proportion of JAK2V617F (Janus Kinase 2) and SF3B1 (Splicing Factor 3B subunit 1) mutations. The purpose of the present study was to analyse the frequency of SF3B1 mutations in a large cohort of 111 patients with RARS-T and 33 patients with RARS and to explore the prognostic impact of SF3B1 mutational status on RARS-T. The frequency of SF3B1 mutations in RARS-T (96/111, 86.5%) and RARS (28/33, 84.8%) was similar. In RARS-T, median survival was better in SF3B1-mutated patients than in SF3B1-non-mutated patients (6.9 and 3.3 years, respectively, P=0.003). RARS can be differentiated from RARS-T by the frequency of JAK2V617F (0% vs 48.6%). In RARS-T patients, SF3B1 (P=0.021) and JAK2 mutations (P=0.016) were independent factors for a better prognosis. Altogether, our results confirm that RARS-T is an independent entity that should be recognised by the next World Health Organisation classification. The assessment of SF3B1 mutations is of prognostic interest in RARS-T patients. Younger age, JAK2V617F and SF3B1 mutations are the main predicting factors for survival in RARS-T.

Introduction

Refractory anaemia with ring sideroblasts (RARS) and marked thrombocytosis (RARS-T) has been proposed in the World Health Organisation 2001 classification of tumours of haematopoietic and lymphoid tissues and retained as a provisional entity in the classification of 2008.1 RARS-T is classified in the myelodysplastic/myeloproliferative (MDS/MPN) disorders group, because it presents with the dysplastic features of RARS2 and the myeloproliferative features of essential thrombocythemia (ET).3 RARS-T is characterised by a high rate of JAK2V617F (Janus Kinase 2) mutations4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and/or the presence of the mutation MPLW515L/R (MyeloProliferative Leukemia).16, 17 The classification of RARS-T as an entity that is independent from RARS or ET is currently a matter of debate. Several specialists favour the hypothesis that RARS-T is a form of ET with ≥15% of ring sideroblasts in the bone marrow18 while others think that RARS-T develops from RARS with secondary thrombocytosis accompanying the acquisition of the JAK2V617F mutation.19

Recent publication from our group in a European retrospective multicentre collaborative study demonstrated that RARS-T was independent from RARS and ET from a clinical and biological as well as prognostic point of view.20

Our results have recently been strengthened by the discovery of the association between myelodysplastic syndromes and mutations involving components of the RNA splicing machinery, including U2AF35 (U2 small nuclear RNA Auxiliary Factor 35), ZRSR2 (Zinc finger CCCH type, RNA-binding motif and Serine/aRginine rich 2), SRSF2 (Serine/aRginine-rich Splicing Factor 2) and SF3B1 (Splicing Factor 3B subunit 1). SF3B1 mutations (SF3B1mut) are found in about 20% of total MDS and correlate strongly with the presence of ≥15% of ring sideroblasts (MDS-RS; 64–82.6% in RARS, 57–76% in refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS) and 66.7–72% in RARS-T).21, 22, 23, 24, 25, 26, 27 On the other hand, mutations of SF3B1 are found at a lower frequency in MDS with <15% ring sideroblasts, which confirms the specificity of SF3B1mut in MDS-RS. SF3B1 mutations are rare in myeloproliferative neoplasms and particularly in ET (0–3%).22, 28 The high frequency of SF3B1 mutations suggests that these mutations have a pathophysiological role in these diseases, probably through perturbations of RNA splicing. The link between SF3B1-mutated status and ring sideroblasts has been confirmed in a recent experimental study on murine models.29 About one quarter of MDS-RS are SF3B1wt and somatic mutations of SRSF2 or ZRSR2 have been described in about 7% of MDS-RS,21 which suggests that other mutant genes may have a role in the appearance of ring sideroblasts. Furthermore, a recent study showed that RARS-T presented with a particular genetic pattern with a high frequency of JAK2V617F and SF3B1 mutations, confirming the classification of RARS-T in the category of myelodysplastic/myeloproliferative neoplasms.30

Finally, as precedent studies have been performed on little RARS-T cohorts, the prognostic impact of SF3B1mut status remains controversial,22, 24, 25, 27, 31 and there is a need for a study on a larger cohort. Our purpose was to analyse the frequency of SF3B1 mutations in a large cohort of 111 RARS-T and to explore the prognostic impact of SF3B1 mutations in this disorder.

Patients and methods

Patient selection

According to the World Health Organisation 2008 classification, patients were diagnosed with RARS-T if they fulfilled the following criteria: (i) anaemia (haemoglobin level <125 g/l for females and <135 g/l for males) with erythroid dysplasia and ≥15% ring sideroblasts; (ii) thrombocytosis of ≥450 × 109 platelets/l; (iii) <5% blast cells in the bone marrow; (iv) the presence of large atypical megakaryocytes similar to those observed in BCR-ABL1-negative myeloproliferative neoplasms; (v) no secondary cause of ring sideroblasts; and (vi) no karyotype abnormalities, such as del(5q), t(3;3)(q21;q26) or inv(3)(q21q26).1

To obtain a comprehensive data set of this rare entity, samples from seven European centres in three European countries were collected. The total cohort comprised 111 cases of RARS-T and 33 cases of RARS.

Data record

For each patient, demographic (gender, age at diagnosis, date of death or last follow-up) and biological data (blood cell count, bone marrow exploration, ring sideroblasts, karyotype, molecular explorations) were collected.

The SF3B1 mutations were analysed with a sensitive next-generation amplicon deep-sequencing assay (454 Life Sciences, Branford, CT, USA) with a median coverage of 500 reads. This approach was able to detect mutations with a sensitivity <1%.

The JAK2V617F mutation was analysed by allele-specific real-time PCR to estimate allele burden according to methods published by Lippert et al.32 and Schnittger et al.33 with a sensitivity of 1%. JAK2exon12 analysis was performed according to the method of Schnittger et al.,34 and the MPLW515 mutations were analysed by high-resolution melting curve analyses followed by Sanger sequencing if positive, as previously published by Schnittger et al.35

Statistical analyses

Standardised overall survival was estimated by the Kaplan–Meier method and based on the time from diagnosis to death or last contact. Survival curves for the different groups were compared using the log rank test. Multivariate analysis was performed using Cox’s proportional hazards model.

Approval for the study was obtained from the ethics committee of each institution, and the procedures were carried out in accordance with the Helsinki Declaration of 1975, as revised in 2000.

Results

Demographic and biological features

A total of 144 cases (111 RARS-T and 33 RARS including 72 males and 72 females) were recorded in the study. Median age at diagnosis was 73.9 years (range: 44.4–96.1 years). The median follow-up was 37.5 and 55.2 months for the RARS-T and RARS cohort, respectively (Table 1). Survival data were available in 130 (97 RARS-T and 33 RARS) of the 144 patients.

Table 1 Demographic and biological characteristics of RARS-T and RARS patients

Frequencies and characterisation of mutations

A karyotype was available in 128 cases. One hundred and ten (85.9%) patients carried a normal karyotype, whereas 18 (14.1%) patients showed aberrant karyotypes, which was equally distributed between RARS-T and RARS patients. Even if the IPSS (International Prognostic Scoring System) score can only be applied to MDS de novo, we calculated it to check if we had a homogeneous group of patients. Most of the patients of the total cohort (133 out of 144) had an IPSS score of 0.

A SF3B1mut was noted in 124 out of the 144 patients (86.1%). A total of 127 SF3B1 mutations were detected in these 124 patients (28 RARS and 96 RARS-T). Three RARS-T cases carried two different mutations. With the exception of one p.Arg549Cys in exon 12 and two in exon 16, all mutations were located in exons 14 and 15. All but one del/ins mutations (p.Met784_Lys785del/insIle) were missense mutations. In detail, the most frequent mutation was p.Lys700Glu (68/127 53.5%), followed by p.Lys666Glu/Thr/Asp/Asn mutations (n=18, 14.2%), p.His662Asp/Gln (n=13, 10.2%), p.Arg625Cys/Leu (n=10, 7.9%), p.Glu622Asp (n=9, 7.1%) and p.Thr663Pro (n=4, 3.1%). Five further mutations were detected in single cases only. Frequencies and positions of mutations are illustrated in Table 1 and Figure 1. Median mutation/wildtype load was 40% (range: 15–78%). Small subclones with SF3B1mut were not detected.

Figure 1
figure1

Positions and characterisation of mutations in the HEAT domains 1–6 (exons 12–16) of the SF3B1 gene. Missense mutations are indicated in green and the rare ins/del mutation in yellow. HEAT, Huntingtin, elongation factor 3, protein phosphatase 2A, Tor1; PPP1R8, protein phosphatase 1, regulatory subunit 8; aa, amino acid.

Frequency of mutations in RARS and RARS-T

The frequency of SF3B1 mutations in RARS-T (96/111, 86.5%) was similar to that in RARS (28/33, 84.8%). By contrast, both entities differed by the presence of the JAK2V617F mutation, which was detected in 54/144 (37.5%) in the total cohort but in 54/111 (48.6%) in RARS-T compared with none (0/33) in RARS (P<0.001). Among the RARS-T SF3B1mut, 46/96 (47.9%) harboured a JAK2V617F mutation. JAK2V617F allele burden was very heterogeneous with a median of 49% (range: 1–100%). No JAK2exon12 mutation (111 tested) was observed, whereas only one case with the MPLW515L mutation was noted in a RARS-T (102 tested; Table 1 and Figure 2).

Figure 2
figure2

Distribution of SF3B1, JAK2V617F and MPLW515L mutations in RARS-T and RARS.

Biological association

The presence of SF3B1mut was analysed with respect to age, sex, white blood cell count, haemoglobin levels, platelet counts, blast counts, percentage of ring sideroblasts, karyotype and JAK2V617F allele burden. In RARS-T, SF3B1 mutations were more frequent in females (56/59, 94.9%) than in males (40/52, 76.9%) (P=0.010), and mean ring sideroblast counts were higher in SF3B1mut than in SF3B1wt (55% vs 38%) (P=0.007). No further correlations were detected for these parameters.

Impact of mutations on outcome

The difference in survival between RARS-T and RARS was not statistically significant (median survival 10.7 vs 6.2 years, respectively, P>0.05). On the other hand, in the total cohort, patients with SF3B1mut had longer survival than those with SF3B1wt (8.0 vs 1.8 years, respectively, P<0.001; Figure 3a). When restricted to RARS-T (85 SF3B1mut and 12 SF3B1wt), median overall survival was 6.9 years in SF3B1mut vs 3.3 years in SF3B1wt (P=0.003; Figure 3b). In RARS, survival was 10.7 years in the SF3B1mut (n=28) and 1.8 years in SF3B1wt patients (n=5; P=0.001; Figure 3c). In RARS-T patients, the survival rates at 2, 4 and 6 years within the JAK2V617F sub-cohort were 94.9, 84.3 and 67.4%, respectively, while within the JAK2wt sub-cohort, they were 79.7, 69.6 and 32.2%, respectively. JAK2V617F (n=50) was then associated with a more favourable outcome compared with JAK2wt (n=47; P=0.019; Figure 3d).

Figure 3
figure3

Kaplan–Meier analysis for survival since diagnosis according to SF3B1 and JAK2V617F mutation status. SF3B1 in (a) total cohort, (b) RARS-T, (c) RARS and (d) JAK2V617F in RARS-T.

Cox regression analysis

In the total cohort including RARS-T and RARS cases in univariate analysis, age (P=0.020), ring sideroblast count (P=0.008) and SF3B1 mutational status (P<0.001) were prognostically significant, but SF3B1 mutational status was the only independent prognostic factor (P=0.001) in multivariable analysis.

In the RARS-T cohort in univariate analysis, age (P=0.038), ring sideroblast count (P=0.014), JAK2V617F (P=0.024) and SF3B1mut (P=0.006) were prognostically significant but only age (P=0.044), JAK2V617F (P=0.016) and SF3B1mut (P=0.021) were independent prognostic parameters in multivariable analysis. Survival was better in patients with age ≤80 years, JAK2V617F and SF3B1 mutations. Taking into account these three prognostic factors, a model for survival in RARS-T patients was constructed in which each risk factor (that is, age >80 years, SF3B1wt and JAK2wt) was worth 1 point and defined two groups of risk: high risk for patients with a score of 2 or 3 (n=13) and low risk when the score is 0 or 1 (n=84). Median survival in the high-risk group was 1.6 vs 8.0 years in the low-risk group (P<0.001; corresponding survival rates at 2, 4 and 6 years are 31.4, 31.4 and 0% for high-risk patients vs 95.8, 84.4 and 62.8% for low-risk patients; Figure 4).

Figure 4
figure4

Kaplan–Meier analysis for survival according to two risk groups. High risk comprising patients with at least two of the following risk factors: age >80 years, SF3B1wt, JAK2wt; and low risk: one or less of the risk factors.

Discussion

Up to now, SF3B1 mutations have been studied in small series of RARS-T patients. In this study, we provide data on SF3B1 mutations in a large cohort of RARS-T patients, which is, to the best of our knowledge, the largest published to date.

SF3B1 mutations were observed with a high frequency in both RARS-T and RARS patients (86.5% and 84.8%, respectively). These proportions are slightly higher than those already published, as SF3B1 mutations have been found in 64–82.6% of RARS21, 22, 23, 24 and 66.7–72% in RARS-T.23, 24 The slightly higher frequency of SF3B1 mutations in the current study may be due to the larger cohort of RARS-T patients than in other studies. There may also be differences in methodology, for example, direct sequencing vs non-sequencing-based screening strategies.

However, RARS differs from RARS-T in that there are no JAK2V617F mutations in RARS,4, 14 whereas there is a high frequency in RARS-T.4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 19 We recently showed that RARS-T differed from RARS and ET from a clinical, biological and prognostic point of view, suggesting that RARS-T could be considered as a unique entity.20 The results of our current study showing the presence of both SF3B1 and JAK2V617F mutations in a high proportion of RARS-T confirm that RARS-T is a unique entity. Indeed, RARS-T was associated with high rates of SF3B1 mutations (86.5%) and JAK2V617F mutations while ET patients have a low frequency of SF3B1 mutations, and in RARS, no JAK2V617F mutations were detected.

A minority of RARS-T patients (13.5%) presented without SF3B1 mutations. This could be due to another mutation affecting components of the RNA splicing machinery as mutations of SRSF2, U2AF35 and ZRSR2 have already been described in 12.4, 7.3 and 3.1% of MDS, respectively,36 or due to mutations of proteins associated with SF3B1 (SF3B4 and SF3B14).

These results are in line with our hypothesis that RARS-T is an independent entity characterised by a particular molecular combination associating mutations that give a myeloproliferative advantage (JAK2V617F, MPLW515R/L or other unknown mutations) and mutations of components of the splicing machinery responsible for myelodysplastic features (SF3B1 in most cases, and possibly SRSF2, U2AF35 or ZRSF2 in the remaining cases).

Conflicting results on the prognostic impact of SF3B1 mutations in MDS have been reported as several studies noted a good prognostic impact in MDS, whereas others hypothesised that SF3B1 mutations were associated with good-prognosis MDS subgroups but lost their prognostic impact in RARS and in RCMD-RS.27

In our large cohort of RARS-T patients, SF3B1 mutations were associated with female sex, higher ring sideroblast counts and a longer overall survival than in SF3B1wt patients. In a multivariable analysis, age >80 years at diagnosis, SF3B1wt as well as JAK2wt were independent factors of a worse prognosis. Based on these three independent parameters, a prognostic score for RARS-T patients was created to define two risk groups: high risk when there were two or three risk factors, low when there was only one or no risk factor. Median survival was 1.6 vs 8.0 years in the high- and low-risk group, respectively, underlying the relevance of such score in RARS-T patients.

Exploring SF3B1 mutations in MDS associated with ring sideroblasts is of interest from a prognostic point of view, particularly as specific treatment will be available.37, 38 Also, allele-specific PCR have been designed, and these could be useful for monitoring minimal residual disease in MDS.39

In summary, this study confirms that RARS-T should be considered an independent entity. In RARS-T patients, age <80 years at diagnosis, SF3B1 and JAK2 mutations are independent factors for better survival and may be used to stratify patients.

References

  1. 1

    Vardiman JW, Bennett JM, Bain BJ, Baumann I, Thiele J, Orazi A . Myelodysplastic/myeloproliferative neoplasms, unclassifiable. In: Swerdlow SH, Campo E, Lee Harris N, Jaffe ES, Pileri SA, Stein H, et al (eds) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue 4th edn. IARC: Lyon, France, 2008; pp 85–86.

  2. 2

    Hasserjian RP, Gatterman N, Bennett JM, Brunning RD, Thiele J . Refractory anemia with ringed sideroblasts. In: Swerdlow SH, Campo E, Lee Harris N, Jaffe ES, Pileri SA, Stein H et al (eds) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue 4th edn. IARC: Lyon, France, 2008; pp 96–97.

  3. 3

    Thiele J, Kvasnicka HM, Orazi A, Tefferi A, Gisslinger H . Essential thrombocythaemia. In: Swerdlow SH, Campo E, Lee Harris N, Jaffe ES, Pileri SA, Stein H et al (eds) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue 4th edn. IARC: Lyon, France, 2008; pp 48–50.

  4. 4

    Ceesay MM, Lea NC, Ingram W, Westwood NB, Gaken J, Mohamedali A et al. The JAK2 V617F mutation is rare in RARS but common in RARS-T. Leukemia 2006; 20: 2060–2061.

  5. 5

    Boissinot M, Garand R, Hamidou M, Hermouet S . The JAK2-V617F mutation and essential thrombocythemia features in a subset of patients with refractory anemia with ring sideroblasts (RARS). Blood 2006; 108: 1781–1782.

  6. 6

    Flach J, Dicker F, Schnittger S, Kohlmann A, Haferlach T, Haferlach C . Mutations of JAK2 and TET2, but not CBL are detectable in a high portion of patients with refractory anemia with ring sideroblasts and thrombocytosis. Haematologica 2010; 95: 518–519.

  7. 7

    Gattermann N, Billiet J, Kronenwett R, Zipperer E, Germing U, Nollet F et al. High frequency of the JAK2 V617F mutation in patients with thrombocytosis (platelet count&gt;600 × 109/L) and ringed sideroblasts more than 15% considered as MDS/MPD, unclassifiable. Blood 2007; 109: 1334–1335.

  8. 8

    Hellstrom-Lindberg E, Cazzola M . The role of JAK2 mutations in RARS and other MDS. Hematology Am Soc Hematol Educ Program 2008;, 52–59.

  9. 9

    Raya JM, Arenillas L, Domingo A, Bellosillo B, Gutierrez G, Luno E et al. Refractory anemia with ringed sideroblasts associated with thrombocytosis: comparative analysis of marked with non-marked thrombocytosis, and relationship with JAK2 V617F mutational status. Int J Hematol 2008; 88: 387–395.

  10. 10

    Remacha AF, Nomdedeu JF, Puget G, Estivill C, Sarda MP, Canals C et al. Occurrence of the JAK2 V617F mutation in the WHO provisional entity: myelodysplastic/myeloproliferative disease, unclassifiable-refractory anemia with ringed sideroblasts associated with marked thrombocytosis. Haematologica 2006; 91: 719–720.

  11. 11

    Renneville A, Quesnel B, Charpentier A, Terriou L, Crinquette A, Lai JL et al. High occurrence of JAK2 V617 mutation in refractory anemia with ringed sideroblasts associated with marked thrombocytosis. Leukemia 2006; 20: 2067–2070.

  12. 12

    Schmitt-Graeff AH, Teo SS, Olschewski M, Schaub F, Haxelmans S, Kirn A et al. JAK2V617F mutation status identifies subtypes of refractory anemia with ringed sideroblasts associated with marked thrombocytosis. Haematologica 2008; 93: 34–40.

  13. 13

    Szpurka H, Tiu R, Murugesan G, Aboudola S, Hsi ED, Theil KS et al. Refractory anemia with ringed sideroblasts associated with marked thrombocytosis (RARS-T), another myeloproliferative condition characterized by JAK2 V617F mutation. Blood 2006; 108: 2173–2181.

  14. 14

    Steensma DP, Tefferi A . JAK2 V617F and ringed sideroblasts: not necessarily RARS-T. Blood 2008; 111: 1748.

  15. 15

    Wang SA, Hasserjian RP, Loew JM, Sechman EV, Jones D, Hao S et al. Refractory anemia with ringed sideroblasts associated with marked thrombocytosis harbors JAK2 mutation and shows overlapping myeloproliferative and myelodysplastic features. Leukemia 2006; 20: 1641–1644.

  16. 16

    Pardanani AD, Levine RL, Lasho T, Pikman Y, Mesa RA, Wadleigh M et al. MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood 2006; 108: 3472–3476.

  17. 17

    Schnittger S, Bacher U, Haferlach C, Dengler R, Krober A, Kern W et al. Detection of an MPLW515 mutation in a case with features of both essential thrombocythemia and refractory anemia with ringed sideroblasts and thrombocytosis. Leukemia 2008; 22: 453–455.

  18. 18

    Wardrop D, Steensma DP . Is refractory anaemia with ring sideroblasts and thrombocytosis (RARS-T) a necessary or useful diagnostic category? Br J Haematol 2009; 144: 809–817.

  19. 19

    Malcovati L, Della Porta MG, Pietra D, Boveri E, Pellagatti A, Galli A et al. Molecular and clinical features of refractory anemia with ringed sideroblasts associated with marked thrombocytosis. Blood 2009; 114: 3538–3545.

  20. 20

    Broseus J, Florensa L, Zipperer E, Schnittger S, Malcovati L, Richebourg S et al. Clinical features and course of refractory anemia with ring sideroblasts associated with marked thrombocytosis. Haematologica 2012; 97: 1036–1041.

  21. 21

    Yoshida K, Sanada M, Shiraishi Y, Nowak D, Nagata Y, Yamamoto R et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature 2011; 478: 64–69.

  22. 22

    Papaemmanuil E, Cazzola M, Boultwood J, Malcovati L, Vyas P, Bowen D et al. Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts. N Engl J Med 2011; 365: 1384–1395.

  23. 23

    Visconte V, Makishima H, Jankowska A, Szpurka H, Traina F, Jerez A et al. SF3B1, a splicing factor is frequently mutated in refractory anemia with ring sideroblasts. Leukemia 2012; 26: 542–545.

  24. 24

    Malcovati L, Papaemmanuil E, Bowen DT, Boultwood J, Della Porta MG, Pascutto C et al. Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms. Blood 2011; 118: 6239–6246.

  25. 25

    Damm F, Thol F, Kosmider O, Kade S, Loffeld P, Dreyfus F et al. SF3B1 mutations in myelodysplastic syndromes: clinical associations and prognostic implications. Leukemia 2012; 26: 1137–1140.

  26. 26

    Damm F, Kosmider O, Gelsi-Boyer V, Renneville A, Carbuccia N, Hidalgo-Curtis C et al. Mutations affecting mRNA splicing define distinct clinical phenotypes and correlate with patient outcome in myelodysplastic syndromes. Blood 2012; 119: 3211–3218.

  27. 27

    Patnaik MM, Lasho TL, Hodnefield JM, Knudson RA, Ketterling RP, Garcia-Manero G et al. SF3B1 mutations are prevalent in myelodysplastic syndromes with ring sideroblasts but do not hold independent prognostic value. Blood 2012; 119: 569–572.

  28. 28

    Visconte V, Makishima H, Maciejewski JP, Tiu RV . Emerging roles of the spliceosomal machinery in myelodysplastic syndromes and other hematological disorders. Leukemia 2012; 26: 2447–2454.

  29. 29

    Visconte V, Rogers HJ, Singh J, Barnard J, Bupathi M, Traina F et al. SF3B1 haploinsufficiency leads to formation of ring sideroblasts in myelodysplastic syndromes. Blood 2012; 120: 3173–3186.

  30. 30

    Jeromin S, Haferlach T, Grossmann V, Alpermann T, Kowarsch A, Haferlach C et al. High frequencies of SF3B1 and JAK2 mutations in refractory anemia with ring sideroblasts associated with marked thrombocytosis strengthen the assignment to the category of myelodysplastic/myeloproliferative neoplasms. Haematologica 2013; 98: 15–17.

  31. 31

    Cazzola M, Rossi M, Malcovati L . Biologic and clinical significance of somatic mutations of SF3B1 in myeloid and lymphoid neoplasms. Blood 2013; 121: 260–269.

  32. 32

    Lippert E, Boissinot M, Kralovics R, Girodon F, Dobo I, Praloran V et al. The JAK2-V617F mutation is frequently present at diagnosis in patients with essential thrombocythemia and polycythemia vera. Blood 2006; 108: 1865–1867.

  33. 33

    Schnittger S, Bacher U, Kern W, Schroder M, Haferlach T, Schoch C . Report on two novel nucleotide exchanges in the JAK2 pseudokinase domain: D620E and E627E. Leukemia 2006; 20: 2195–2197.

  34. 34

    Schnittger S, Bacher U, Haferlach C, Geer T, Muller P, Mittermuller J et al. Detection of JAK2 exon 12 mutations in 15 patients with JAK2V617F negative polycythemia vera. Haematologica 2009; 94: 414–418.

  35. 35

    Schnittger S, Bacher U, Haferlach C, Beelen D, Bojko P, Burkle D et al. Characterization of 35 new cases with four different MPLW515 mutations and essential thrombocytosis or primary myelofibrosis. Haematologica 2009; 94: 141–144.

  36. 36

    Thol F, Kade S, Schlarmann C, Loffeld P, Morgan M, Krauter J et al. Frequency and prognostic impact of mutations in SRSF2, U2AF1, and ZRSR2 in patients with myelodysplastic syndromes. Blood 2012; 119: 3578–3584.

  37. 37

    Rymond B . Targeting the spliceosome. Nat Chem Biol. 2007; 3: 533–535.

  38. 38

    Webb TR, Joyner AS, Potter PM . The development and application of small molecule modulators of SF3b as therapeutic agents for cancer. Drug Discov Today 2013; 18: 43–49.

  39. 39

    Matsuda K, Ishida F, Ito T, Nakazawa H, Miura S, Taira C et al. Spliceosome-related gene mutations in myelodysplastic syndrome can be used as stable markers for monitoring minimal residual disease during follow-up. Leuk Res 2012; 36: 1393–1397.

Download references

Acknowledgements

We thank the Medical Doctors from the Haematology Department and Laboratory of the University Hospital of Dijon, the Spanish Group of Hematological Cytology (GECH), as well as Philip Bastable for revising the manuscript. EL and FL are grateful to the Tumor Bank of the CHU of Bordeaux. This work was supported by grants from the association ‘Tulipes contre le cancer’ (Châlon s/Saône, Burgundy, France) and from FEHH (Spain) and 2009 SGR 541 (Generalitat de Catalunya).

Author information

Correspondence to F Girodon or S Schnittger.

Ethics declarations

Competing interests

SS and TH declare part ownership of the MLL Munich Leukemia Laboratory. TA, SJ and VG are employed by the MLL Munich Leukemia Laboratory. All the other authors declare no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Broséus, J., Alpermann, T., Wulfert, M. et al. Age, JAK2V617F and SF3B1 mutations are the main predicting factors for survival in refractory anaemia with ring sideroblasts and marked thrombocytosis. Leukemia 27, 1826–1831 (2013) doi:10.1038/leu.2013.120

Download citation

Keywords

  • refractory anaemia with ring sideroblasts and marked thrombocytosis
  • SF3B1
  • prognostic impact
  • survival

Further reading