Co-occurrence of type I CALR and two MPL mutations in patient with primary myelofibrosis

Tashkandi, Hammad; Moore, Erika M.; Tomlinson, Benjamin; Goebel, Teresa E.

doi:10.1007/s00277-017-3022-x

Cited by 6 publications

(5 citation statements)

References 10 publications

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“…28 The remaining patientderived second-site mutations were all identified as enhancers of S505N in our second-site screen and are therefore likely to be particularly strong MPN drivers. Additional published reports of patients with double mutations include V501A1W515R, 18 V501A1W515L, 18 and S505C1W515L, 18,19 and we identified a second instance of each of these combinations in our patient cohorts ( Figure 2D). Finally, we note that any of these mutations could occur on the background of additional mutations in other domains of TpoR that are known to modulate function, such as P106L or S204P/F in the extracellular domain and Y591F/N in the intracellular cytoplasmic tail, 2 which we have not evaluated here.…”

Section: Resultssupporting

confidence: 71%

“…11,13 Previous studies have identified patients with a canonical MPL exon 10 mutation and additional exon 10 mutations on the same allele. 18,19 Whether these confer qualitatively or quantitatively different cellular phenotypes from the single canonical mutations is unclear. To test how second-site mutations in the TpoR TMD may modulate the activity of a known driver mutation, we performed a second DMS screen on the S505N background ( Figure 2A), often found as a germline mutation in hereditary thrombocythemia.…”

Section: Resultsmentioning

confidence: 99%

“…W515L/K/R/A mutations destroy an inhibitory site that prevents activation when Tpo is not bound, 5,[9][10][11] whereas S505N activates TpoR by driving strong dimerization. 6,12,13 Other "noncanonical" MPL exon 10 mutations have been identified in patients, [14][15][16][17][18][19][20] but, in most cases, their functional consequences and relevance to disease are unknown. Here, we report 2 deep-sequencing-based saturation mutagenesis screens in which we examined all possible single amino acid substitutions in the TpoR TMD and identified novel mutations that cause constitutive TpoR activation or enhance S505N-driven activation in Ba/F3 cells.…”

Section: Introductionmentioning

confidence: 99%

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Novel drivers and modifiers of MPL-dependent oncogenic transformation identified by deep mutational scanning

Bridgford

Lee

et al. 2020

Blood

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The single transmembrane domain (TMD) of the human thrombopoietin receptor (TpoR/myeloproliferative leukemia [MPL] protein), encoded by exon 10 of the MPL gene, is a hotspot for somatic mutations associated with myeloproliferative neoplasms (MPNs). Approximately 6% and 14% of JAK2 V617F− essential thrombocythemia and primary myelofibrosis patients, respectively, have “canonical” MPL exon 10 driver mutations W515L/K/R/A or S505N, which generate constitutively active receptors and consequent loss of Tpo dependence. Other “noncanonical” MPL exon 10 mutations have also been identified in patients, both alone and in combination with canonical mutations, but, in almost all cases, their functional consequences and relevance to disease are unknown. Here, we used a deep mutational scanning approach to evaluate all possible single amino acid substitutions in the human TpoR TMD for their ability to confer cytokine-independent growth in Ba/F3 cells. We identified all currently recognized driver mutations and 7 novel mutations that cause constitutive TpoR activation, and a much larger number of second-site mutations that enhance S505N-driven activation. We found examples of both of these categories in published and previously unpublished MPL exon 10 sequencing data from MPN patients, demonstrating that some, if not all, of the new mutations reported here represent likely drivers or modifiers of myeloproliferative disease.

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Section: Resultssupporting

confidence: 71%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Novel drivers and modifiers of MPL-dependent oncogenic transformation identified by deep mutational scanning

Bridgford

Lee

et al. 2020

Blood

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“…1 To date, only one case of coexisting CALR and MPL mutations in a Ph-MPN has been reported. 2 The presence of a BCR-ABL1 translocation with a coexisting mutation of CALR or MPL is also exceptionally rare, with only 7 cases reported in the literature. [3][4][5][6][7][8][9] Here, we report the first documented case of a patient with Ph+ chronic myeloid leukemia (CML) harboring both CALR and MPL mutations.…”

Section: Chronic Myeloid Leukemia Bcr-abl1-positive With Calr and Mpmentioning

confidence: 99%

Chronic myeloid leukemia, BCR‐ABL1‐positive with CALR and MPL mutations

Klairmont

Cheng

Schwartzberg

et al. 2018

Int J Lab Hematology

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“…However, the presence of additional genetic alterations possibly contributing to disease initiation and progression was not investigated [ 16 , 17 , 18 ]. Furthermore, these reports failed to establish if the observed genetic alterations were in cis (on the same allele) or in trans (on two different alleles) [ 11 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

Additional Genetic Alterations and Clonal Evolution of MPNs with Double Mutations on the MPL Gene: Two Case Reports

et al. 2023

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Essential thrombocythemia (ET) and primary myelofibrosis (PMF) are two of the main BCR-ABL1-negative chronic myeloproliferative neoplasms (MPNs) characterized by abnormal megakaryocytic proliferation. Janus kinase 2 (JAK2) mutations are detected in 50–60% of ET and PMF, while myeloproliferative leukemia (MPL) virus oncogene mutations are present in 3–5% of cases. While Sanger sequencing is a valuable diagnostic tool to discriminate the most common MPN mutations, next-generation sequencing (NGS) is a more sensitive technology that also identifies concurrent genetic alterations. In this report, we describe two MPN patients with simultaneous double MPL mutations: a woman with ET presenting both MPLV501A-W515R and JAK2V617F mutations and a man with PMF displaying an uncommon double MPLV501A-W515L. Using colony-forming assays and NGS analyses, we define the origin and mutational landscape of these two unusual malignancies and uncover further gene alterations that may contribute to the pathogenesis of ET and PMF.

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Co-occurrence of type I CALR and two MPL mutations in patient with primary myelofibrosis

Cited by 6 publications

References 10 publications

Novel drivers and modifiers of MPL-dependent oncogenic transformation identified by deep mutational scanning

Novel drivers and modifiers of MPL-dependent oncogenic transformation identified by deep mutational scanning

Chronic myeloid leukemia, BCR‐ABL1‐positive with CALR and MPL mutations

Additional Genetic Alterations and Clonal Evolution of MPNs with Double Mutations on the MPL Gene: Two Case Reports

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