Landscape of RAS pathway mutations in patients with myelodysplastic syndrome/myeloproliferative neoplasm overlap syndromes: a study of 461 molecularly annotated patients

Buradkar, Ajinkya; Bezerra, Evandro D.; Coltro, Giacomo; Lasho, Terra L.; Finke, Christy; Gangat, Naseema; Carr, Ryan M.; Binder, Moritz; Mangaonkar, Abhishek A.; Ketterling, Rhett P.; Khan, Shakila P.; Rodriguez, Vilmarie; Tefferi, Ayalew; Patnaik, Mrinal M.

doi:10.1038/s41375-020-0889-7

Cited by 7 publications

(4 citation statements)

References 10 publications

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“…Myeloproliferative features were present in 4/10 patients, with: MDS/MPN-U with prominent eosinophilia in patient 6, megacaryocytic hyperplasia with fibrosis in patients 8 and 10, and MP-CMML in patient 11. The presence of myeloproliferative features in these four patients could be accounted for by genetics only in patient 6, who carried multiple RAS-pathway mutations [ 15 ], and in patient 11, who showed a typical mutational signature of proliferative CMML, with a classical combination of epigenetically targeted and Ras-pathway gene mutations [ 16 ]. The genetic lesion causing the eosinophilia of patient 6 was not evident, having ruled out, by FISH, the fusion transcripts of PDGFRα, PDGFRβ, and band 8p11, as well as the PCM1-JAK2 fusion, and, by NGS, the presence of JAK2exon13indel; it is noteworthy that this patient had a “second hit” in ETV6 by a missense point mutation at an allele frequency of 14%, probably abolishing completely ETV6 function in a subclone of the disease [ 6 ].…”

Section: Case Series Presentationmentioning

confidence: 99%

Description of an Institutional Cohort of Myeloid Neoplasms Carrying ETV6-Locus Deletions or ETV6 Rearrangements

Papadopoulou¹,

Schoumans²,

Scarpelli³

et al. 2023

Acta Haematol

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The gene encoding for transcription factor ETV6 presents recurrent lesions in hematologic neoplasms, most notably the ETV6-RUNX1 rearrangement in childhood B-ALL. The role of ETV6 for normal hematopoiesis is unknown, but loss of its function probably participates in oncogenic procedures. In myeloid neoplasms, ETV6-locus (12p13) deletions are rare but recurrent; ETV6 translocations are even rarer, but those reported seem to have phenotype-defining consequences. We herein describe the genetic and hematologic profile of myeloid neoplasms with ETV6 deletions (10 cases), or translocations (4 cases) diagnosed in the last ten years in our institution. We find complex karyotype to be the most prevalent one among patients with 12p13 deletion (8/10 patients), with most frequent coexisting anomalies being monosomy 7 or deletion 7q32 (5/10), monosomy 5 or del5q14-15 (5/10) and deletion/inversion of chromosome 20 (5/10), and most frequent point-mutation being TP53 mutation (6/10 patients). Mechanisms of synergy of these lesions are unknown. We describe the entire genetic profile and hematologic phenotype of cases with extremely rare ETV6 translocations, confirming the biphenotypic T/myeloid nature of acute leukemia associated to ETV6-NCOA2 rearrangement, the association of t (1;12) (p36;p13) and of the CHIC2-ETV6 fusion with MDS/AML, and the association of the ETV6-ACSL6 rearrangement with myeloproliferative neoplasm with eosinophilia. Mutation of the intact ETV6 allele was present in two cases and seems to be subclonal to the chromosomal lesions. Decoding the mechanisms of disease related to ETV6 haploinsufficiency or rearrangements is important for the understanding of pathogenesis of myeloid neoplasms and fundamental research must be guided by observational cues.

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Section: Case Series Presentationmentioning

confidence: 99%

Description of an Institutional Cohort of Myeloid Neoplasms Carrying ETV6-Locus Deletions or ETV6 Rearrangements

Papadopoulou¹,

Schoumans²,

Scarpelli³

et al. 2023

Acta Haematol

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Section: Myelodysplastic/myeloproliferative Neoplasm With Ring Sideroblasts and Thrombocytosismentioning

confidence: 99%

“…The MPN component subsequently develops with the acquisition of signaling mutations, most commonly JAK2 V617F (50%), with MPL and SH2B3 mutations being infrequent (<10%) 102. Of note, RAS pathway mutations and CALR mutations are very uncommon in MDS/MPN-RS-T 103. 4 | CONCLUSIONMDS-RS and MDS/MPN-RS-T are myeloid neoplasms synonymous with the presence of BM RS and the presence of SF3B1 mutations.…”

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confidence: 99%

Myelodysplastic syndromes with ring sideroblasts (MDS‐RS) and MDS/myeloproliferative neoplasm with RS and thrombocytosis (MDS/MPN‐RS‐T) – “2021 update on diagnosis, risk‐stratification, and management”

Patnaik

Tefferi

2021

American J Hematol

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Disease Overview Ring sideroblasts (RS) are erythroid precursors with abnormal perinuclear mitochondrial iron accumulation. Two myeloid neoplasms defined by the presence of RS, include myelodysplastic syndromes with RS (MDS‐RS) and MDS/myeloproliferative neoplasm with RS and thrombocytosis (MDS/MPN‐RS‐T). Diagnosis MDS‐RS is a lower risk MDS, with single or multilineage dysplasia (MDS‐RS‐SLD/MLD), <5% bone marrow (BM) blasts, <1% peripheral blood blasts and ≥15% BM RS (≥5% in the presence of SF3B1 mutations). MDS/MPN‐RS‐T, now a formal entity in the MDS/MPN overlap syndromes, has diagnostic features of MDS‐RS‐SLD, along with a platelet count ≥450 × 109/L and large atypical megakaryocytes. Mutations and Karyotype Mutations in SF3B1 are seen in ≥80% of patients with MDS‐RS‐SLD and MDS/MPN‐RS‐T, and strongly correlate with the presence of BM RS; MDS/MPN‐RS‐T patients also demonstrate JAK2V617F (50%), DNMT3A, TET2 and ASXL1 mutations. Cytogenetic abnormalities are uncommon in both. Risk Stratification Most patients with MDS‐RS‐SLD are stratified into lower risk groups by the revised‐IPSS. Disease outcome in MDS/MPN‐RS‐T is better than that of MDS‐RS‐SLD, but worse than that of essential thrombocythemia (MPN). Both diseases are associated with a low risk of leukemic transformation. Treatment Anemia and iron overload are complications seen in both and are managed similar to lower risk MDS and MPN. Luspatercept, a first‐in‐class erythroid maturation agent is now approved for the management of anemia in patients with MDS‐RS and MDS/MPN‐RS‐T. Aspirin therapy is reasonable in MDS/MPN‐RS‐T, especially in the presence of JAK2V617F, but the value of platelet‐lowering drugs remains to be defined.

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“…Mutations in genes belonging to the RAS signaling pathway, including NRAS, KRAS, and CBL, are also relatively common in CMML. RAS-related gene mutations are more closely related to the proliferative phenotype of CMML and have been reported to have a negative impact on prognosis [12,30,[42][43][44][45]. However, this poor prognostic impact of RAS pathway alterations does not rule out the possibility that the proliferative phenotype of the mutant group and concomitant mutation in high-risk genes such as ASXL1 are affected.…”

Section: Genetic Characterizationmentioning

confidence: 99%

Diagnosis and treatment of chronic myelomonocytic leukemia

Kwon

2021

Blood Res

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Chronic myelomonocytic leukemia (CMML) is a clonal disorder of hematopoietic cells and is a complex of heterogeneous conditions with both myeloproliferative and myelodysplastic features. The diagnosis of CMML is made using morphologic criteria including monocyte-dominant leukocytosis, dysplastic changes, and increased blasts in the bone marrow. Recently, the identification of monocyte subtypes in peripheral blood using multiparameter flow cytometry has been actively studied. Chromosomal abnormalities are the basis of CMML risk stratification, and mutations in several genes including ASXL1 are known to be important not only for the diagnosis and treatment of this disease but also for predicting its prognosis. The standard treatment principles for CMML have not yet been clearly defined; however, hypomethylating agents are mainly considered the frontline therapy in most cases. Although allogeneic hematopoietic stem cell transplantation has limited applications owing to its toxicity, it still plays an important role as the only curative treatment option. Researchers are continuing to develop new drugs for CMML treatment and to prove their clinical usefulness. This review summarizes what is known to date on the diagnosis, treatment, and prognostic factors of CMML and presents future directions by analyzing recent research trends.

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Landscape of RAS pathway mutations in patients with myelodysplastic syndrome/myeloproliferative neoplasm overlap syndromes: a study of 461 molecularly annotated patients

Cited by 7 publications

References 10 publications

Description of an Institutional Cohort of Myeloid Neoplasms Carrying ETV6-Locus Deletions or ETV6 Rearrangements

Description of an Institutional Cohort of Myeloid Neoplasms Carrying ETV6-Locus Deletions or ETV6 Rearrangements

Myelodysplastic syndromes with ring sideroblasts (MDS‐RS) and MDS/myeloproliferative neoplasm with RS and thrombocytosis (MDS/MPN‐RS‐T) – “2021 update on diagnosis, risk‐stratification, and management”

Diagnosis and treatment of chronic myelomonocytic leukemia

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