Fast Facts: Myeloproliferative Neoplasms

By R.A. Mesa and C.N. Harrison

Presentation of the myeloproliferative neoplasms (MPNs) varies widely, and correct diagnosis and management can be challenging, and is becoming more complex as understanding of the underlying molecular basis for these disorders emerges. Appropriate management is increasingly informed by accurate risk stratification founded on understanding of cytogenetic and molecular markers, as well as the clinical presentation. 'Fast Facts: myeloproliferative neoplasms' focuses on the three most common chronic MPNs: • Essential thrombocythemia (ET) – characterized by increased platelet count • Polycythemia vera (PV) – characterized by excessive production of red blood cells • Primary myelofibrosis – a more severe and heterogenous disorder that may overlap with ET and PV but is commonly associated with anemia. Written by two leading experts in the field, Fast Facts: myeloproliferative neoplasms provides concise, up-to-date and practical guidance on the accurate diagnosis, risk stratification and management of these MPNs. It also provides key insights into our growing understanding of the underlying molecular and genetic basis of these disorders, and how this is informing risk stratification and management strategies. This concise handbook will be invaluable to clinicians, medical students, nurses, pharmacists and scientists in understanding and overcoming the everyday and rarer challenges associated with MPN.

• Language: English
• Publisher: S. Karger
• Release date: Feb 11, 2019
• ISBN: 9781910797808

Book preview

Introduction

The myeloproliferative neoplasms (MPNs) are a group of disorders characterized by excessive proliferation of hematopoietic precursor cells in the bone marrow and over-production of mature blood cells. According to the current World Health Organization classification, these include Philadelphia chromosome (BCR-ABL1)-positive chronic myeloid leukemia, chronic neutrophilic leukemia, polycythemia vera, primary myelofibrosis (prefibrotic and overt), essential thrombocythemia, chronic eosinophilic leukemia, not otherwise specified, and MPN, unclassifiable.

This book focuses on the three Philadelphia chromosome-negative MPNs (sometimes described as the classical or chronic MPNs), which share a number of clinical and molecular features:

• essential thrombocythemia

• polycythemia vera

• primary myelofibrosis.

These are the most common MPNs, and are associated with frequent complications such as venous and arterial thrombosis, hemorrhage and transformation to acute myeloid leukemia. The presentation of these MPNs varies widely, and diagnosis and management can be challenging. This book provides concise, up-to-date practical guidance on the accurate diagnosis, risk stratification and management of these disorders. It will be invaluable to clinicians, medical students, nurses, pharmacists and scientists in understanding and overcoming the everyday and rarer challenges associated with MPN.

All myeloproliferative neoplasms (MPNs) are believed to originate from a single hematopoietic stem cell bearing one or more genetic mutations that subsequently undergoes clonal expansion; this is accompanied by hyperplasia of single or multiple hematopoietic cell lineages.

• Essential thrombocythemia (ET) is characterized by an increased platelet count, associated with megakaryocytic hyperplasia.

• Polycythemia vera (PV) is predominantly characterized by excessive erythrocyte production, with variable megakaryocytic and granulocytic hyperplasia.

• Primary myelofibrosis (PMF) is a more heterogeneous disorder, characterized by bone marrow fibrosis with megakaryocytic and granulocytic hyperplasia and erythroid hypoplasia.

The genetic basis of these MPNs has been elucidated over the last two decades but emerging evidence suggests that non-genetic factors such as age and inflammation also play important roles in their development and progression.

Genetic basis

Driver mutations. The MPNs are caused by driver mutations in the Janus kinase 2 (JAK2), myeloproliferative leukemia virus oncogene (MPL) or calreticulin (CALR) genes (Table 1.1). JAK2 and CALR mutations are most commonly involved, although the distribution of driver mutations differs in ET, PV and PMF (Figure 1.1). In general, these mutations are mutually exclusive (e.g. the presence of a JAK2 mutation largely precludes MPL or CALR mutations) and predominantly present only in MPNs (described as MPN restricted). Non-restricted mutations found in other myeloid disorders are also found in MPNs, such as mutations of ASXL1.

JAK2 mutations. JAK2 is a tyrosine kinase that activates downstream signaling via erythropoietin, granulocyte colony-stimulating factor receptors and thrombopoietin receptors (the three principal myeloid cytokine receptors) (Figure 1.2). Activation of these receptors triggers increased signaling via the STAT (signal transducer and activator of transcription)-5, MAPK (mitogen-activated protein kinase) and PI3K (phosphatidylinositol 3-kinase) pathways.

The most common JAK2 mutation, V617F, results in substitution of phenylalanine for valine at position 617, which appears to render hematopoietic cells more sensitive to growth factors such as erythropoietin and thrombopoietin. The JAK2V617F mutation is present in approximately 70% of MPNs, but 95% of cases of PV.

Figure 1.1 Distribution of JAK2, MPL and CALR driver mutations in essential thrombocythemia, polycythemia vera and primary myelofibrosis. CALR, calreticulin; JAK, Janus kinase; MPL, myeloproliferative leukemia virus oncogene. Adapted from Klampfl et al., 2013.¹

A small proportion of individuals with PV have mutations in JAK2 exon 12, particularly those who do not have the JAK2V617F mutation. Although these JAK2 mutations are not usually associated with PMF, they can lead to the development of post-PV myelofibrosis. JAK2 mutation-negative PV can occur but is rare.

MPL mutations. The MPL gene encodes the thrombopoietin receptor. The most common MPL mutations implicated in MPNs – designated W515L, W515K and W515R – are missense mutations affecting a tryptophan residue at the boundary between the transmembrane and cytosolic domains of the receptor. These mutations are present in only 3–5% of individuals with ET or PMF. A further mutation, MPLS505N, is present in fewer than 1% of ET cases.

CALR mutations. The CALR gene encodes calreticulin, a multifunctional protein that acts as a calcium storage protein in the endoplasmic reticulum and as a molecular chaperone, facilitating the folding and unfolding of proteins and other macromolecules. Frameshift mutations in the CALR gene are present in 50–60% of individuals with ET and 75% of those with PMF who do not have JAK2 or MPL mutations. More than 50 different mutations in the CALR gene have been reported, all located in exon 9, where they cause +1 frameshifts, resulting in MPL activation. The two most common mutations result in the deletion of 52 base pairs (type 1) or the insertion of five base pairs (type 2); all other mutations are classified as type 1-like or type 2-like, depending on their effect on the calreticulin C-terminus.³ Type 1 mutations are most common.

Figure 1.2 Activation of cytokine receptors by JAK2V617F and CALR mutations. (a) JAK2V617F activates signaling via the homodimeric EPOR (involved in erythropoiesis), MPL (involved in thrombocytosis) and G-CSFR (granulopoiesis). This mutation can therefore give rise to the phenotypes seen in all three MPNs.

(b) CALR mutations primarily activate MPL (although G-CSFR may be activated at low levels), and have no effect on erythropoiesis; they therefore produce a phenotype dominated by thrombocytosis (essential thrombocythemia or primary myelofibrosis). Akt, protein kinase B; CALR, calreticulin; EPOR, erythropoietin receptor; G-CSFR, granulocyte colony-stimulating factor receptor; JAK2, Janus kinase 2; MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositol 3-kinase; STAT5, signal transducer and activator of transcription 5; TPOR, thrombopoietin receptor. Adapted from Vainchenker & Kralovics, 2017.²

Triple-negative MPN has features consistent with MPN (typically ET or PMF; rarely PV) but lacks one of the common driver mutations. It is a heterogeneous condition: some cases may be hereditary thrombocytosis,² some have rarer mutations in JAK2, MPL or non-driver genes and some patients have no detectable mutations.

Non-driver mutations have also been implicated in the initiation and progression of MPNs. These include mutations affecting:

• intracellular signaling pathways

• epigenetic regulators such as DNA methylators and histone modifiers

• transcription factors

• RNA splicing.

The involvement of these genes in disease initiation and progression is summarized in Table 1.2. Although most of these mutations are uncommon, some may be present in up to 25% of PMF cases.