The kinetics of clonal dominance in myeloproliferative disorders

Catlin, Sandra N.; Guttorp, Peter; Abkowitz, Janis L.

doi:10.1182/blood-2005-03-1240

Cited by 49 publications

(48 citation statements)

References 31 publications

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“…At the end, homozygous cells fully dominate hematopoiesis (clonal dominance). 32 In terms of JAK2 (V617F) mutant alleles, the first step is characterized by a progressive increase from 0% to 50%, whereas the second step involves a transition from 50% to 100%. Based on simple mathematical calculations, when mutant alleles are more than 75%, the majority of hematopoietic cells (Ͼ 50%) are by definition homozygous for JAK2 (V617F).…”

Section: Discussionmentioning

confidence: 99%

Relation between JAK2 (V617F) mutation status, granulocyte activation, and constitutive mobilization of CD34+ cells into peripheral blood in myeloproliferative disorders

Passamonti

Rumi

Pietra

et al. 2006

Blood

234

244

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We studied the relationship between granulocyte JAK2 (V617F) mutation status, circulating CD34 ؉ cells, and granulocyte activation in myeloproliferative disorders. Quantitative allele-specific polymerase chain reaction (PCR) showed significant differences between various disorders with respect to either the proportion of positive patients (53%-100%) or that of mutant alleles, which overall ranged from 1% to 100%. In polycythemia vera, JAK2 (V617F) was detected in 23 of 25 subjects at diagnosis and in 16 of 16 patients whose disease had evolved into myelofibrosis; median percentages of mutant alleles in these subgroups were significantly different (32% versus 95%, P < .001). Circulating CD34 ؉ cell counts were variably elevated and associated with disease category and JAK2 (V617F) mutation status. Most patients had granulocyte activation patterns similar to those induced by administration of granulocyte colonystimulating factor. A JAK2 (V617F) gene dosage effect on both CD34 ؉ cell counts and granulocyte activation was clearly demonstrated in polycythemia vera, where abnormal patterns were mainly found in patients carrying more than 50% mutant alleles. These observations suggest that JAK2 ( IntroductionPhiladelphia-negative (Ph Ϫ ) chronic myeloproliferative disorders include polycythemia vera (PV), essential thrombocythemia (ET), and chronic idiopathic myelofibrosis (CIMF). 1 Diagnostic criteria for these conditions were been redefined a few years ago by the World Health Organization (WHO) classification, 2 which considers bone marrow biopsy as an essential procedure for diagnosis of ET and CIMF and as a complementary procedure for diagnosis of PV. According to the WHO criteria, CIMF can be subdivided into a prefibrotic stage (p-CIMF) and a fibrotic stage (f-CIMF); from a clinical standpoint, the p-CIMF mimics ET. 3 A gain-of-function mutation of the Janus kinase 2 (JAK2) gene has been recently reported in myeloproliferative disorders. [4][5][6][7][8] The currently available data indicate that JAK2 (V617F) participates in the pathogenesis of these conditions. 6 Although the mutation's precise place in the hierarchical order of events remains to be established, gain of function and loss of control appear to be the essential features of the excessive myeloproliferation associated with JAK2 (V617F). 9 Abnormal trafficking of CD34 ϩ cells with increased counts in the peripheral blood is found not only in CIMF but also in advanced stages of PV and ET. [10][11][12] It has been recently demonstrated that bone marrow-repopulating cells and more differentiated progenitor cells are constitutively mobilized into the peripheral blood in CIMF and that their differentiation program is abnormal. 13 Additional studies have suggested that the marrow milieu of patients with CIMF is characterized by a proteolytic environment that contributes to CD34 ϩ cell mobilization. 14 Activation of signaling by the JAK2 (V617F) mutation is associated with altered gene expression in granulocytes from patients with myeloproliferative disorde...

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Section: Discussionmentioning

confidence: 99%

Relation between JAK2 (V617F) mutation status, granulocyte activation, and constitutive mobilization of CD34+ cells into peripheral blood in myeloproliferative disorders

Passamonti

Rumi

Pietra

et al. 2006

Blood

234

244

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“…Similar conclusions were reached by a second group using a stochastic model of myeloproliferative neoplasms in small animals in which hematopoiesis has been well-characterized. 56 The introduction of a single neoplastic stem cell in the model led to clonal predominance in only ϳ 15%-20% of simulations. Assumptions about normal hematopoietic stem cells may not always be applicable to CML stem cells.…”

Section: Stem-cell Exhaustionmentioning

confidence: 99%

Minimal Residual Disease and Discontinuation of Therapy in Chronic Myeloid Leukemia: Can We Aim at a Cure?

Melo

Ross

2011

Hematology

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Patients with chronic myeloid leukemia (CML) who have achieved a complete molecular response (CMR) defined by no detectable BCR-ABL mRNA on imatinib (IM) treatment often ask whether it is necessary for treatment to continue. We now know that approximately 40% of patients with a stable CMR for at least 2 years are able to stop IM treatment and remain in molecular remission for at least 2 years. This exciting observation has raised hopes that many patients can be cured of CML without the need for transplantation and its attendant risks. One might argue that for many patients maintenance therapy with IM or an alternative kinase inhibitor is so well tolerated that there is no imperative to stop treatment; however, chronic medical therapy may be associated with impaired quality of life and reduced compliance. Inferences about the biology of CML in patients responding to kinase inhibitors can be drawn from clinical experience, molecular monitoring data, and experimental observations. We summarize this information herein, and propose 3 possible pathways to "cure" of CML by kinase inhibitors: stem-cell depletion, stem-cell exhaustion, and immunological control.

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“…On a functional level, acquisition of clonal dominance represents a competitive advantage in the bone marrow microenvironment, as suggested by stochastic models (2). A requisite property for clonal dominance is the ability to self-renew.…”

Section: Introductionmentioning

confidence: 99%

Csf3r mutations in mice confer a strong clonal HSC advantage via activation of Stat5

Liu¹,

Kunter²,

Krem³

et al. 2008

J. Clin. Invest.

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A fundamental property of leukemic stem cells is clonal dominance of the bone marrow microenvironment. Truncation mutations of CSF3R, which encodes the G-CSF receptor (G-CSFR), are implicated in leukemic progression in patients with severe congenital neutropenia. Here we show that expression of a truncated mutant Csf3r in mice confers a strong clonal advantage at the HSC level that is dependent upon exogenous G-CSF. G-CSF-induced proliferation, phosphorylation of Stat5, and transcription of Stat5 target genes were increased in HSCs isolated from mice expressing the mutant Csf3r. Conversely, the proliferative advantage conferred by the mutant Csf3r was abrogated in myeloid progenitors lacking both Stat5A and Stat5B, and HSC function was reduced in mice expressing a truncated mutant Csf3r engineered to have impaired Stat5 activation. These data indicate that in mice, inappropriate Stat5 activation plays a key role in establishing clonal dominance by stem cells expressing mutant Csf3r.

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The kinetics of clonal dominance in myeloproliferative disorders

Abstract: To study clonal evolution in myeloproliferative disorders, we used stochastic models of hematopoiesis for mouse and cat, species for which the in vivo kinetics of hematopoietic stem cells (

Cited by 49 publications

References 31 publications

Relation between JAK2 (V617F) mutation status, granulocyte activation, and constitutive mobilization of CD34+ cells into peripheral blood in myeloproliferative disorders

Relation between JAK2 (V617F) mutation status, granulocyte activation, and constitutive mobilization of CD34+ cells into peripheral blood in myeloproliferative disorders

Minimal Residual Disease and Discontinuation of Therapy in Chronic Myeloid Leukemia: Can We Aim at a Cure?

Csf3r mutations in mice confer a strong clonal HSC advantage via activation of Stat5

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