The prognostic advantage of calreticulin mutations in myelofibrosis might be confined to type 1 or type 1-like CALR variants

Tefferi, Ayalew; Lasho, Terra L.; Tischer, Alexander; Wassie, Emnet A.; Finke, Christy; Belachew, Alem A.; Ketterling, Rhett P.; Hanson, Curtis A.; Pardanani, Animesh

doi:10.1182/blood-2014-07-588426

Cited by 136 publications

(127 citation statements)

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“…PMF refers to BCR‐ABL1 ‐negative MPN, and is a clonal disorder of haematopoiesis arising in the haematopoietic stem cell (HSC) 2. The majority of patients with PMF carry mutations that activate JAK–STAT signalling; 60% harbour the JAK2V617F mutation, approximately 30% carry a calreticulin (CALR) mutation, and 8% carry a myeloproliferative leukaemia virus oncogene ( MPL ) mutation 3, 4, 5, 6, 7, 8. PMF is the most aggressive of the three classic MPNs, and is associated with significantly shortened survival 9, 10.…”

Section: Bone Marrow Fibrosismentioning

confidence: 99%

Understanding deregulated cellular and molecular dynamics in the haematopoietic stem cell niche to develop novel therapeutics for bone marrow fibrosis

Gleitz

Kramann

Schneider

2018

The Journal of Pathology

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Bone marrow fibrosis is the continuous replacement of blood‐forming cells in the bone marrow with excessive scar tissue, leading to failure of the body to produce blood cells and ultimately to death. Myofibroblasts are fibrosis‐driving cells and are well characterized in solid organ fibrosis, but their role and cellular origin in bone marrow fibrosis have remained obscure. Recent work has demonstrated that Gli1+ and leptin receptor+ mesenchymal stromal cells are progenitors of fibrosis‐causing myofibroblasts in the bone marrow. Genetic ablation or pharmacological inhibition of Gli1+ mesenchymal stromal cells ameliorated fibrosis in mouse models of myelofibrosis. Conditional deletion of the platelet‐derived growth factor (PDGF) receptor‐α (PDGFRA) gene (Pdgfra) and inhibition of PDGFRA by imatinib in leptin receptor+ stromal cells suppressed their expansion and ameliorated bone marrow fibrosis. Understanding the cellular and molecular mechanisms in the haematopoietic stem cell niche that govern the mesenchymal stromal cell‐to‐myofibroblast transition and myofibroblast expansion will be critical to understand the pathogenesis of bone marrow fibrosis in both malignant and non‐malignant conditions, and will guide the development of novel therapeutics. In this review, we summarize recent discoveries of mesenchymal stromal cells as part of the haematopoietic niche and as myofibroblast precursors, and discuss potential therapeutic strategies in the specific targeting of fibrotic transformation in bone marrow fibrosis. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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Section: Bone Marrow Fibrosismentioning

confidence: 99%

Understanding deregulated cellular and molecular dynamics in the haematopoietic stem cell niche to develop novel therapeutics for bone marrow fibrosis

Gleitz

Kramann

Schneider

2018

The Journal of Pathology

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“…In ET, type 2 CALR mutation is associated with significantly higher platelet count [42] and, in PMF, with higher risk category, circulating blast percentage, leukocyte count, and inferior survival [43]. CALR variants that are neither type 1 nor type 2 are operationally classified into "type 1-like" and "type 2-like" variants, based on their structural similarities to type 1 and type 2 CALR variants, respectively, which is in turn based on alpha-helix content of the mutant C-terminus [44]. Most noteworthy is the survival advantage shown by PMF patients with type 1 or type 1-like CALR variants, compared to all other genotypes [44].…”

Section: Phenotypic Correlates Of Driver Mutationsmentioning

confidence: 99%

“…CALR variants that are neither type 1 nor type 2 are operationally classified into "type 1-like" and "type 2-like" variants, based on their structural similarities to type 1 and type 2 CALR variants, respectively, which is in turn based on alpha-helix content of the mutant C-terminus [44]. Most noteworthy is the survival advantage shown by PMF patients with type 1 or type 1-like CALR variants, compared to all other genotypes [44]. Most recently, the order of mutation acquisition was suggested as an additional determinant of phenotype in MPN [45].…”

Section: Phenotypic Correlates Of Driver Mutationsmentioning

confidence: 99%

“…More recently, a number of DIPSS-plus-independent risk factors in PMF were identified and they include driver mutations other than type 1 or type 1-like CALR variants [44], monosomal karyotype [74], nullizygosity for JAK2 46/1 haplotype [75], low JAK2V617F allele burden [76,77], presence or number [78] of IDH1/2 [51], EZH2 [51], SRSF2 [51], or ASXL1 mutations [51], and increased serum IL-8 [79], IL-2R [79] or serum free light chain levels [80]. In a recent international study of 570 patients with PMF [81], the authors reported the longest …”

Section: Advances In Prognosticationmentioning

confidence: 99%

“…Such patients can further be classified into "very low risk" and "low risk" but their management is mostly similar (Fig. 2) [44]. There is no evidence to support the value of specific therapy in asymptomatic patients with DIPSS-plus low or intermediate 1 risk disease.…”

Section: Myelofibrosismentioning

confidence: 99%

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Myeloproliferative neoplasms: A decade of discoveries and treatment advances

2015

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Myeloproliferative neoplasms (MPN) are clonal stem cell diseases, first conceptualized in 1951 by William Dameshek, and historically included chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). In 1960, Nowell and Hungerford discovered an invariable association between the Philadelphia chromosome (subsequently shown to harbor the causal BCR‐ABL1 mutation) and CML; accordingly, the term MPN is primarily reserved for PV, ET, and PMF, although it includes other related clinicopathologic entities, according to the World Health Organization (WHO) classification system. In 2005, William Vainchenker and others described a Janus kinase 2 mutation (JAK2V617F) in MPN and this was followed by a series of additional descriptions of mutations that directly or indirectly activate JAK‐STAT: JAK2 exon 12, myeloproliferative leukemia virus oncogene (MPL) and calreticulin (CALR) mutations. The discovery of these, mostly mutually exclusive, “driver” mutations has contributed to revisions of the WHO diagnostic criteria and risk stratification in MPN. Mutations other than JAK2, CALR and MPL have also been described in MPN and shown to provide additional prognostic information. From the standpoint of treatment, over the last 50 years, Louis Wasserman from the Unites States and Tiziano Barbui from Italy had skillfully organized and led a number of important clinical trials, whose results form the basis for current treatment strategies in MPN. More recently, allogeneic stem cell transplant, as a potentially curative treatment modality, and JAK inhibitors, as palliative drugs, have been added to the overall therapeutic armamentarium in myelofibrosis. In the current review, I will summarize the important advances made in the last 10 years regarding the science and practice of MPN. Am. J. Hematol. 91:50–58, 2016. © 2015 Wiley Periodicals, Inc.

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Selecting patients with primary myelofibrosis for stem cell transplant using clinical, mutational, and transplant‐specific profiles

Gagelmann

2020

Adv Cell Gene Ther

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As with other hematologic malignancies, the management of patients with MF has very much entered the molecular era. The prognostic impact of several driver and nondriver mutations is now well-established; this has obvious relevance to both patient selection for allogeneic hematopoietic cell transplantation and posttransplant outcomes. For transplant, present JAK2 or triple-negative driver mutation genotype together with present ASXL1 mutation may provide best utility for counseling patients with respect to posttransplant outcome, together with clinical (performance status, age, and leukocyte and platelet counts) and transplant-related factors (donor relation). Different conditioning intensities do not seem to play a role with regards to outcome posttransplant but still need to be compared in the molecular era. While ruxolitinib provides clinical benefits for patients before transplant, more studies on the finetuning and integration of ruxolitinib into the transplant algorithm are needed.In conclusion, as clinically important risk stratification has been achieved throughout the disease course and new targeted agents become increasingly available, a collaborative and integrative approach is needed to translate new biological insights to personalized/tailored and timed therapy for patients with myelofibrosis.

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The prognostic advantage of calreticulin mutations in myelofibrosis might be confined to type 1 or type 1-like CALR variants

Cited by 136 publications

References 8 publications

Understanding deregulated cellular and molecular dynamics in the haematopoietic stem cell niche to develop novel therapeutics for bone marrow fibrosis

Understanding deregulated cellular and molecular dynamics in the haematopoietic stem cell niche to develop novel therapeutics for bone marrow fibrosis

Myeloproliferative neoplasms: A decade of discoveries and treatment advances

Selecting patients with primary myelofibrosis for stem cell transplant using clinical, mutational, and transplant‐specific profiles

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