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Progenitor genotyping reveals a complex clonal architecture in a subset of CALR ‐ mutated myeloproliferative neoplasms
Author(s) -
Martin Sarah,
Wright Casey M.,
Scott Linda M.
Publication year - 2017
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.14512
Subject(s) - calreticulin , mutation , myelofibrosis , myeloproliferative neoplasm , biology , genetics , frameshift mutation , essential thrombocythemia , myeloproliferative disorders , germline mutation , cancer research , polycythemia vera , immunology , gene , bone marrow , endoplasmic reticulum
Summary The identification of acquired CALR mutations in patients with essential thrombocythaemia ( ET ) or myelofibrosis ( MF ) has meant that disease‐initiating mutations can now be detected in about 90% of all patients with a myeloproliferative neoplasm ( MPN ). Here, we show that only those CALR mutations that cause a +1 frameshift, thereby altering the carboxy‐terminus of calreticulin, promote cytokine independence in vitro; in‐frame deletions were not functional, and are unlikely to be the pathogenetic mutation underlying some MPN cases. Expression of the thrombopoietin receptor, MPL , was also necessary for factor‐independence. Although the CALR mutations are considered to occur only in JAK 2 V617F‐negative cases and in a heterozygous state, progenitor genotyping revealed that this is not always true. Notably, CALR mutation‐positive MPN s can be polyclonal: in one case, two distinct CALR mutation‐positive subpopulations could be identified; in another, separate populations of JAK 2 V617F‐positive and CALR ‐mutated cells were present. Mitotic recombination involving chromosome 19 in a third instance resulted in the emergence of a CALR mutation‐homozygous subclone. Collectively, our studies demonstrate that occasional patients with CALR mutation‐positive ET or MF carry other MPN ‐initiating genetic mutations (including JAK 2 V617F), acquire “secondary mutations” before or after the CALR mutation, or evolve over time to being CALR mutation‐homozygous.