Mutant calreticulin in myeloproliferative neoplasms

How, Joan; Hobbs, Gabriela; Mullally, Ann

doi:10.1182/blood.2019000622

Cited by 63 publications

(70 citation statements)

References 70 publications

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“…The mechanism of oncogenesis mediated by mutant CALR has been unraveled; the latter binds to and activates the TPO receptor, MPL, resulting in phosphorylation of JAK2 and constitutive activation of JAK/STAT signaling. [45][46][47][48][49][50] Activation of the TPO receptor requires the glycan binding site and a novel C-terminal tail of mutant calreticulin. 46 It is also known that cell surface expression of the mutated CALR-MPL complex is a mandatory feature for MPL activation and JAK/STAT signaling.…”

Section: Jak-stat Signaling and Beyondmentioning

confidence: 99%

Myelofibrosis biology and contemporary management

Gangat

Tefferi

2020

Br J Haematol

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Myelofibrosis is an enigmatic myeloproliferative neoplasm, despite noteworthy strides in understanding its genetic underpinnings. Driver mutations involving JAK2, CALR or MPL in 90% of patients mediate constitutive JAK-STAT signaling which, in concert with epigenetic alterations (ASXL1, DNMT3A, SRSF2, EZH2, IDH1/2 mutations), play a fundamental role in disease pathogenesis. Aberrant immature megakaryocytes are a quintessential feature, exhibiting reduced GATA1 protein expression and secreting a plethora of pro-inflammatory cytokines (IL-1 ß, TGF-ß), growth factors (b-FGF, PDGF, VEGF) in addition to extra cellular matrix components (fibronectin, laminin, collagens). The ensuing disrupted interactions amongst the megakaryocytes, osteoblasts, endothelium, stromal cells and myofibroblasts within the bone marrow culminate in the development of fibrosis and osteosclerosis. Presently, prognostic assessment tools for primary myelofibrosis (PMF) are centered on genetics, with incorporation of cytogenetic and molecular information into the mutation-enhanced (MIPSS 70-plus version 2.0) and genetically-inspired (GIPSS) prognostic scoring systems. Both models illustrate substantial clinical heterogeneity in PMF and serve as the crux for riskadapted therapeutic decisions. A major challenge remains the dearth of disease-modifying drugs, whereas allogeneic transplant offers the chance of long-term remission for some patients. Our review serves to synopsise current appreciation of the pathogenesis of myelofibrosis together with emerging management strategies.

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Section: Jak-stat Signaling and Beyondmentioning

confidence: 99%

Myelofibrosis biology and contemporary management

Gangat

Tefferi

2020

Br J Haematol

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“…Interestingly, the outcome of patients with activated UPR was more favorable, as they displayed a lower relapse rate and a better overall/disease-free survival [97]. It should be considered that calreticulin is an ER chaperone protein involved in protein folding quality control and Ca2 + homeostasis [100,101]. When calreticulin was overexpressed in human U937 AML cells, it blocked the translation of C/EBPα, thereby negatively affecting myeloid differentiation [102].…”

Section: Upr Involvement In Amlmentioning

confidence: 99%

The Unfolded Protein Response: A Novel Therapeutic Target in Acute Leukemias

Martelli

Paganelli

Chiarini

et al. 2020

Cancers

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The unfolded protein response (UPR) is an evolutionarily conserved adaptive response triggered by the stress of the endoplasmic reticulum (ER) due, among other causes, to altered cell protein homeostasis (proteostasis). UPR is mediated by three main sensors, protein kinase RNA-like endoplasmic reticulum kinase (PERK), activating transcription factor 6α (ATF6α), and inositol-requiring enzyme-1α (IRE1α). Given that proteostasis is frequently disregulated in cancer, UPR is emerging as a critical signaling network in controlling the survival, selection, and adaptation of a variety of neoplasias, including breast cancer, prostate cancer, colorectal cancer, and glioblastoma. Indeed, cancer cells can escape from the apoptotic pathways elicited by ER stress by switching UPR into a prosurvival mechanism instead of cell death. Although most of the studies on UPR focused on solid tumors, this intricate network plays a critical role in hematological malignancies, and especially in multiple myeloma (MM), where treatment with proteasome inhibitors induce the accumulation of unfolded proteins that severely perturb proteostasis, thereby leading to ER stress, and, eventually, to apoptosis. However, UPR is emerging as a key player also in acute leukemias, where recent evidence points to the likelihood that targeting UPR-driven prosurvival pathways could represent a novel therapeutic strategy. In this review, we focus on the oncogene-specific regulation of individual UPR signaling arms, and we provide an updated outline of the genetic, biochemical, and preclinical therapeutic findings that support UPR as a relevant, novel target in acute leukemias.

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“…In contrast, type 2 mutations more commonly lead to ET and have higher platelet counts than type 1 CALR ET. However, in primary myelofibrosis, type 2 mutations confer a similar phenotype to JAK2 V617F -positive MF and have more pronounced splenomegaly, circulating blasts and cytopenia than the type 1 CALR counterpart [57]. CALR is not associated with a polycythemia phenotype [49].…”

Section: Calr (Calreticulin)mentioning

confidence: 97%

“…and type 1-like mutations lead to complete loss of all negatively charged amino acids. The second is type 2 (5-bp insertion), and type 2-like mutations eliminate approximately half of the negatively charged amino acid sequences [ 57 , 58 ]. The type of mutation confers some phenotypic differences, with type 1 mutations seen more commonly in primary myelofibrosis and is associated with a lower DIPSS score, suggesting a more favourable prognosis in comparison to other forms of PMF.…”

Section: Calr (Calreticulin)mentioning

confidence: 99%

MPN: The Molecular Drivers of Disease Initiation, Progression and Transformation and their Effect on Treatment

Grabek

Straube

Bywater

et al. 2020

Cells

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Myeloproliferative neoplasms (MPNs) constitute a group of disorders identified by an overproduction of cells derived from myeloid lineage. The majority of MPNs have an identifiable driver mutation responsible for cytokine-independent proliferative signalling. The acquisition of coexisting mutations in chromatin modifiers, spliceosome complex components, DNA methylation modifiers, tumour suppressors and transcriptional regulators have been identified as major pathways for disease progression and leukemic transformation. They also confer different sensitivities to therapeutic options. This review will explore the molecular basis of MPN pathogenesis and specifically examine the impact of coexisting mutations on disease biology and therapeutic options.

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Mutant calreticulin in myeloproliferative neoplasms

Abstract: In a Blood Spotlight that is also this month’s CME article, the authors review the current understanding of the biology underpinning mutant CALR-driven myeloproliferative neoplasms, discuss its clinical implications, and highlight future therapeutic approaches.

Cited by 63 publications

References 70 publications

Myelofibrosis biology and contemporary management

Myelofibrosis biology and contemporary management

The Unfolded Protein Response: A Novel Therapeutic Target in Acute Leukemias

MPN: The Molecular Drivers of Disease Initiation, Progression and Transformation and their Effect on Treatment

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