Mutated clones driving leukemic transformation are already detectable at the single cell level in CD34-positive cells in the chronic phase of primary myelofibrosis

Parenti, Sandra; Rontauroli, Sebastiano; Carretta, Chiara; Mallia, Selene; Genovese, Elena; Chiereghin, Chiara; Peano, Clelia; Tavernari, Lara; Bianchi, Elisa; Fantini, Sebastian; Sartini, Stefano; Romano, Oriana; Bicciato, Silvio; Tagliafico, Enrico; Porta, Matteo Giovanni Della; Manfredini, Rossella

doi:10.1101/2020.12.07.414177

Cited by 3 publications

(3 citation statements)

References 31 publications

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“…In this study, we demonstrated that PD-L1 expression was significantly associated with overt myelofibrosis, JAK2V617F, high WBC counts, and HMR mutations as defined by MIPSS70+ in PMF patients. Our findings coincide with a recent report in which PD-L1 expression was increased, along with reduced T-cell activation, during disease progression in a PMF patient, as demonstrated by single cell analysis of hematopoietic stem cells [27]. Likewise, PD-L1 expression has been shown to be an independent prognosis marker in several solid cancers [28][29][30].…”

Section: Discussionsupporting

confidence: 92%

PD‐L1 expression in megakaryocytes and its clinicopathological features in primary myelofibrosis patients

Lee

Lin

Wei

et al. 2021

The Journal of Pathology CR

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Myeloproliferative neoplasms (MPNs) are characterized by upregulation of proinflammatory cytokines and immune dysregulation, which provide a reasonable basis for immunotherapy in patients. Megakaryocytes are crucial in the pathogenesis of primary myelofibrosis (PMF), the most clinically aggressive subtype of MPN. In this study, we aimed to explore PD-L1 (programmed death-ligand 1) expression in megakaryocytes and its clinical implications in PMF. We analyzed PD-L1 expression on megakaryocytes in PMF patients by immunohistochemistry and correlated the results with clinicopathological features and molecular aberrations. We employed a twotier grading system considering both the proportion of cells positively stained and the intensity of staining. Among the 85 PMF patients, 41 (48%) showed positive PD-L1 expression on megakaryocytes with the immunereactive score ranging from 1 to 12. PD-L1 expression correlated closely with higher white blood cell count (p = 0.045), overt myelofibrosis (p = 0.010), JAK2V617F mutation (p = 0.011), and high-molecular risk mutations (p = 0.045), leading to less favorable overall survival in these patients (hazard ratio 0.341, 95% CI 0.135-0.863, p = 0.023). Our study provides unique insights into the interaction between immunologic and molecular phenotypes in PMF patients. Future work to explore the translational potential of PD-L1 in the clinical setting is needed.

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Section: Discussionsupporting

confidence: 92%

PD‐L1 expression in megakaryocytes and its clinicopathological features in primary myelofibrosis patients

Lee

Lin

Wei

et al. 2021

The Journal of Pathology CR

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“…One important question is whether these latter leukemias originated from an antecedent clonal hematopoiesis of indeterminate potential (CHIP), different from the one that established the chronic phase MPN. Single cell studies reinforce the extreme complexity and heterogeneity of leukemic evolution in MF with multiple subclones branching from the originating leukemic clone [41,42].…”

Section: Mutational Impact On Disease Phenotype and Therapeutic Respo...mentioning

confidence: 66%

Biological drivers of clinical phenotype in myelofibrosis

et al. 2022

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Myelofibrosis (MF) is a myeloproliferative disorder that exhibits considerable biological and clinical heterogeneity. At the two ends of the disease spectrum are the myelodepletive or cytopenic phenotype and the myeloproliferative phenotype. The cytopenic phenotype has a high prevalence in primary MF (PMF) and is characterized by low blood counts. The myeloproliferative phenotype is typically associated with secondary MF (SMF), mild anemia, minimal need for transfusion support, and normal to mild thrombocytopenia. Differences in somatic driver mutations and allelic burden, as well as the acquisition of non-driver mutations further influences these phenotypic differences, prognosis, and response to therapies such as JAK2 inhibitors. The outcome of patients with the cytopenic phenotype are comparatively worse and frequently pose a challenge to treat given the inherent exacerbation of cytopenias. Recent data indicate that an innate immune deregulated state that hinges on the myddosome-IRAK-NFκB axis favors the cytopenic myelofibrosis phenotype and offers opportunity for novel treatment approaches. We will review the biological and clinical features of the MF disease spectrum and associated treatment considerations.

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“…Conversely, a positive prognostic effect of CALR mutations has been reported, particularly of type-1 CALR , provided that it is not associated with ASXL1 aberrancy, although the real prognostic impact of CALR subvariants is still controversial in this clinical setting [ 2 , 78 , 79 , 80 ]. More generally, the overall number of mutations frequently increase upon progression and have an impact on outcome [ 12 ]; however, at least some of the mutated clones that effectively drive the transformation may already be present in the chronic phase [ 81 ]. The mutational profiles of MPN-AP and MPN-BP are similar but are markedly different from those of both de novo AML and MPN-CP [ 71 , 82 ].…”

Section: Leukemic Progressionmentioning

confidence: 99%

Progression in Ph-Chromosome-Negative Myeloproliferative Neoplasms: An Overview on Pathologic Issues and Molecular Determinants

Sabattini

Pizzi

Agostinelli

et al. 2021

Cancers

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Progression in Ph-chromosome-negative myeloproliferative neoplasms (MPN) develops with variable incidence and time sequence in essential thrombocythemia, polycythemia vera, and primary myelofibrosis. These diseases show different clinic-pathologic features and outcomes despite sharing deregulated JAK/STAT signaling due to mutations in either the Janus kinase 2 or myeloproliferative leukemia or CALReticulin genes, which are the primary drivers of the diseases, as well as defined diagnostic criteria and biomarkers in most cases. Progression is defined by the development or worsening of marrow fibrosis or the progressive increase in the marrow blast percentage. Progression is often related to additional genetic aberrations, although some can already be detected during the chronic phase. Detailed scoring systems for clinical usage that are mostly applied in patients with primary myelofibrosis have been defined, and the most recent ones include cytogenetic and molecular parameters with prognostic significance. Additional different clinic-pathologic changes have been reported that may occur during the course of the disease and that are, at present, classified as WHO-defined types of progression, although they likely represent such an event. The present review is meant to provide an updated overview on progression in Ph-chromosome-negative MPN, with a major focus on the pathologic side.

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Mutated clones driving leukemic transformation are already detectable at the single cell level in CD34-positive cells in the chronic phase of primary myelofibrosis

Cited by 3 publications

References 31 publications

PD‐L1 expression in megakaryocytes and its clinicopathological features in primary myelofibrosis patients

PD‐L1 expression in megakaryocytes and its clinicopathological features in primary myelofibrosis patients

Biological drivers of clinical phenotype in myelofibrosis

Progression in Ph-Chromosome-Negative Myeloproliferative Neoplasms: An Overview on Pathologic Issues and Molecular Determinants

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