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V617F+

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Mutant allele

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Mutant allele

Myeloproliferative neoplasms 103

V617F+

Water

Normal

Control

Mutant specic

(B)

Figure7.2 Detection of the JAK2V617F mutation. (A) Allele- specific polymerase chain reaction (PCR). Amplification with primers P1 and P3yields a product of 364 bp (control), whereas amplification with primers P1 and P2 yields a 203 bp PCR product from the mutant allele only. (B)Real- time PCR using a dual- labeled probe specific for the mutant allele. Amplification from the wild- type allele results in displacement but not destruction ofthe probe, resulting in no release of fluorescence. In contrast, amplification from the mutant allele results in Taq - dependent destruction of the probe, releasing the reporter (R) whose fluorescence can then be detected.

Phylogenetic reconstruction of MPN driver mutation acquisition and evolution has been elegantly performed by the group of Nangalia and colleagues at Cambridge

∆Rm

0.001

0.0001

0.1

0.01

22 24 26 28 30

32 34 36 38 40

JAK2

Normal

thrombotic risks to prevent those who develop MPN and thrombotic complications later in life. Evaluation in clinical

trials would be warranted. University. Here, using samples from MPN patients, they delineated the timing of mutation occurrence, clonal selection, and evolution. Phylogenetic trees were established for each patient by detecting single nucleotide variants (SNV) across colonies. By definition, each individual had a differing phylogenetic tree and branching structure, but commonalities were noted. Parallel clonal evolution was identified frequently– i.e. similar genetic changes happening in different HSC populations. Intriguingly, this analysis revealed that JAK2 V617F was acquired in utero or early childhood in some of these individuals with an average latency period to disease development of 31

years; this was modified by the presence of other mutations and highly heterogenous rates of clonal expansion. Of note, the earliest acquisition was only several weeks following conception. As discussed by the authors, the key to further understanding and decisions onintervention may involve a dual approach: early detection of low allele burden mutant clones and an estimation of theircompetitive rate of growth. They additionally suggest that early detection may help guide the management on

Other JAK2 mutations

JAK2 exon12mutations

In general, around 2–3% of patients with annotated PV lack the JAK2 V617F mutation. JAK2 exon 12 mutations were first described in 2007in “JAK2 negative polycythemia” and have not been described in either ET or PMF. Exon 12 codes for amino acids 505–547 and is located in a “linker region,” situated between the JAK2 SH2 and JH2 domains. Multiple mutations have been described in exon 12 leading to erythrocytosis, spanning a region from residues 536–547 (Figure7.3). The most frequent mutations described from one comprehensive study of 33 patients from the Mayo clinic and University of Florence were the H538- K539delins (n= 8; 24%), F537- K539delins (n = 6; 18%), N542- E543delins (n= 5; 15%), and E543- D544del (n= 5; 15%). Murine models transduced to express one such human mutation, JAK2- N542- E543del, displayed increased erythropoiesis, with

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70 75 80

–1

(A)

Kinase Pseudokinase

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104 Molecular Hematology

(B)

–5

HRM difference plot

Figure7.3 Types and detection of JAK2 exon 12mutations. (A)Three main types of mutation can be described: lysine to leucine substitution at codon 539 (shaded); deletion of glutamic acid at codon 543 (shaded); duplication affecting codons 537–546 (underlined). (B)Detection of JAK2 exon 12mutations by high- resolution melting analysis. Source: Frequency of mutations taken from Passamonti, F., Elena, C., Schnittger, S., etal. (2011). Molecular and clinical features of the myeloproliferative neoplasm associated with JAK2 exon 12mutations. Blood 117:2813–6.

Normal

K539L

F537-K539delinsL

N542-E543del

E543-D544del

F537-I546dupF547

normal white cell and platelet counts. No increased reticulin deposition or aberrant megakaryocytopoiesis was evident. Expression led to increased baseline levels of both phosphoSTAT3 and phosphor- ERk1/2. Of note, these models confirmed evidence of low hepcidin levels together with elevated Transferrin receptor protein 1 (Tfr1) expression, favoring redirection of iron to “fuel” erythroid precursors.

Phenotypically, JAK2 exon 12 PV patients tend to be younger and may have higher Hgb levels than those with JAK2 V617F mutations, but this is not a consistent finding.

It appears more common to have an isolated erythrocytosis, lacking a concomitant leukocytosis or thrombocytosis, compared to JAK2 V617F PV. Exon 12 PV cases may lack the classical PV features on bone marrow trephine evaluation. Most have evidence of marked erythroid hyperplasia and small, atypical megakaryocytes tend to be present with a lack of clustering in comparison to the megakaryocytic atypia and panmyelosis, most frequently seen with JAK2 V617F mutated PV. Of particular note, there appears to be no significant difference in thrombosis risk, overall survival, or risk of myelofibrotic transformation/blast phase evolution when compared to JAK2 V617F PV.

JAK2 variants and eosinophilia

A novel mutation due to a common 4- AA deletion and variable 1- AA insertion (Leu583- Ala586DelInsSer/Gln/Pro) within the JAK2 JH2 domain has been recently described in four patients with eosinophilia, two of whom had the Leu583Ala586DelInsSer (JAK2ex13InDel), and interestingly met the criteria for both chronic eosinophilic leukemia (CEL) and PV, highlighting the degree of phenotypic heterogeneity from variant JAK2 mutations with a novel PV/CEL MPN.

Germline JAK2 mutations

A number of gain- of- function germline JAK2 mutations, located predominantly in the kinase or pseudokinase domains, have been described associated with hereditary thrombocytosis. For example, the Oxford group reported on kindred with familial thrombocytosis due to a germline JAK2 V617I mutation. Functional analysis revealed limited constitutive activation but markedly reduced threshold for cytokine- induced activation. Of note, a case of JAK2 FERM domain variant associated with hereditary thrombocytosis has also recently been described.

JAK2 germline haplotype

In 2009, three separate groups described an association between a germline haplotype involving the 3′- section of JAK2 termed the “GGCC or 46/1 haplotype.” It can be represented by four main SNPs, (rs1159782, rs3780367, rs10974944, and rs12343867). This is a low penetrance predisposition allele that maps to chromosome 9p and contains three genes JAK2, Insulin- like 6 (INSL6), and Insulin- like 4 (INSL4). This 46/1haplotype can associate with some but not all JAK2 mutated MPN, in particular PV, and also nonJAK2 mutated MPN and was not initially believed to be a major player in driving particular clinicopathological characteristics. More recently, Tefferi and colleagues reevaluated the phenotypic and prognostic relevance of the JAK2 46/1haplotype in 414 annotated Primary MF cases. The JAK2 46/1 haplotype was present in 69% of included

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Myeloproliferative neoplasms 105

S505(A)

–1

–2

–3

–4

–5

–6

–7

–8

–9

79.5 80.0 80.5 81.0 81.5 82.0 82.5 83.0 83.5 84.0 84.5 85.0 85.5 86.0 86.5 87.0 87.5 88.0

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Extracellular TM Cytoplasmic

(B)

HRM difference plot

W515

Normal

W515L

W515A

S505N

W515K

W515R

Figure7.4 Detection of MPL exon 10mutations. (A) The S505 and W515 amino acid residues lie within the transmembrane domain (TM) and juxtamembrane domain (JM), respectively. (B) Detection of MPL exon 10mutations by high- resolution melting analysis.

patients (44% in a heterozygous state and 25% in a homozygous state). Homozygous JAK2 46/1 haplotype was more common in JAK2 mutated PMF, whereas heterozygous and nullizygous states were more common in CALR mutated MF. There was no significant difference in distribution across Dynamic IPSS risk groups (a dynamic prognostic score for primary MF that can be applied at any stage in the disease course and not just at the time of diagnosis) as determined by JAK2 46/1 haplotype status. Of particular interest, this study confirmed the association of nullizygosity for JAK2 46/1 haplotype with inferior overall survival and this was independent of karyotype and high molecular risk mutations. Links with thrombosis and symptom burden still require clarification.

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MPL mutations in ET and MF

Mutations in the gene for the TPO receptor, MPL, were first reported in 2006, and have since been found in 5–10% of patients with PMF and 1–4% of patients with ET. MPL protein has three structural domains: an extracellular domain, where

its ligand, TPO, binds; a transmembrane spanning helix; and an intracellular region composed of a flexible juxtamembrane region followed by a protein kinase domain and a C- terminal region. In MPN, the most prominent mutations in MPL cluster in exon 10, affecting the transmembrane and juxtamembrane domains of MPL (Figure 7.4). The most common mutations are W515L and W515K, but other variants at the W515 residue have been identified (W515A and W515R). These mutations result in the substitution of tryptophan for another amino acid in the transmembrane domain of MPL. The loss of tryptophan is suggested to decrease the MPL helix tilt angle relative to the lipid bilayer, bringing the dimer into active conformation in the absence of ligand binding. The S505N variant was originally described in hereditary thrombocytosis but has more recently been found as an acquired mutation in ET and PMF. S505N mutation induces both a change in receptor conformation and signal activation in the absence of ligand binding. While mutations of W515 and S505N operate through different mechanisms, they both result in TPO receptor activation in the absence of TPO binding, leading to the MPN phenotype. Whole- exome sequencing has identified further MPL gain- of- function mutations located

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outside of exon 10, including S204F/P and Y591F/N. Many patients acquire homozygous MPL mutations, but some patients are found tohave multiple MPL mutations, or MPL mutation in combination with JAK2 V617F or CALR mutation albeit this is very rare.

MPL mutations can confer cytokine- independent proliferation in cell lines. Introduction of W515L or W515A mutations into murine bone marrow was associated withmarked thrombocytosis, splenomegaly, extramedullary hematopoiesis, and MF. There was minimal effect on reticulocytes, in keeping with a selective effect on megakaryocyte precursors and the observation that these mutations are not associated with PV in humans. Patients with MPL- mutated MF are more likely to be female, older, with more severe anemia and more constitutional symptoms than MPLunmutated MF. While patients with MPL- mutated ET tend to present with higher platelet counts, lower hemoglobin levels, and lower white cell counts than patients with JAK2 V617F- positive ET. Patients with MPL- mutant ET also have a higher risk of thrombosis and an increased rate of progression to PET- MF compared to JAK2V617F- positive ET.

CALR mutations in ET and MF

Calreticulin (CALR) is a highly conserved, multifunctional protein that acts as a molecular chaperone. It normally resides

also shuttle between other cellular compartments. Functionally, it acts as a “chaperone” for polypeptides to ensure that they are folded into the correct configuration in the ER prior to transport to the Golgi apparatus for secretion. It also plays an important functional role in calcium homeostasis.

In 2013, two different groups published on the discovery of mutations in CALR using massive parallel sequencing in ET/MF patients lacking a JAK2 or MPL mutation. The most prevalent mutation is known as a Type 1mutation, characterized by a 529 followed in prevalence by a Type 2 mutation, a 5- bp TTGTC insertion (p.K385fs*47) in exon 9; together these account for >80% of all CALR mutations described in MPN (Figure7.5) All CALR mutations induce a +1 bp frameshift within the codon- reading frame of the DNA, leading to the generation of a mutant CALR protein which has a positively charged C- terminal amino acid sequence; of note Type 1 mutations eliminate all negatively charged amino acids (AA)in the C- terminus and Type 2 to a lesser extent when compared to the wild- type protein. More than 50mutations in CALR have been described to date, most commonly small insertions or deletions clustered within exon 9 and can be classified as “Type- 1 like” and “Type- 2 like.” Mutations induce loss of an ER- retention signal (KDEL motif) and Ca++ binding domain, coupled with structural conformational

base pair (bp) deletion (p.L367fs*46) in exon

changes in the N- domain and altered glycan binding sites, leading to export of CALR from the ER. Mutant CALR acquires the ability to bind to the extracellular domain of MPL in the absence of TPO, a lectin- dependent function is required, with consequent activation of the MPL- JAK- STAT signaling axis. Pro- survival and anti- apoptotic pathways are upregulated.

Compared to JAK2 mutated ET, both Type 1 and 2 CALR mutations associated with higher platelet counts, lower white cell counts, and lower hemoglobin. A comparative analysis has been retrospectively performed to delineate if any differences exist dependent on type of mutation in ET. Type 2mutation associated with higher platelet count and younger age, and Type 1 with male sex. In MF, in general, CALR mutations are associated with a more indolent phenotype, most commonly in younger males, with less thrombotic riskand better overall survival when comparing those with Type 1 CALR mutant MF to those who have JAK2 or MPL mutated MF. More recent MF prognostic scoring systems incorporating molecular annotation, such as the MutationEnhanced International Prognostic Scoring System 70+ v2.0 (MIPSS70v.2.0), MYSEC- PM, and the individualized sanger prognostic calculator incorporate CALR mutation status, alongside other clinicopathological findings, as a prognostic factor. Novel therapeutic approaches targeting mutant CALR MPN include neoepitope- directed monoclonal antibodies and vaccinations are undergoing evaluation as potential future therapeutic strategies.

Other somatic mutations in ET, MF,and PV

Additional somatic mutations may be found both in those with driver mutations in JAK2, CALR, and MPL and those without (so- called “triple- negative” MPN), with around 30–40% of patients harboring additional somatic mutations. Of note, studies have observed that MPN has an overall lower burden of somatic mutations (∼0.2 somatic mutations per Mb) compared with other hematological malignancies (e.g.

0.37mutations per Mb for AML and ∼1mutation per Mb for multiple myeloma). An increased number of “nonmutations is associated with older age, and more advanced disease, with ET and PV patients having fewer mutations on average that those with MF. Most often, the implicated genes affect hematopoietic stem cell differentiation and proliferation, and unsurprisingly are also seen in other myeloid malignancies and in those with CHIP, with ASXL1, DNMT3A, and TET2 being the three most commonly mutated genes. Mutations in genes involved in DNA methylation such as DNMT3A (a methyltransferase), TET2, and IDH1/2 (encoding proteins involved in demethylation) may promote or inhibit HSC differentiation dependent on context. Monoallelic

driver”

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Myeloproliferative neoplasms 107

c.1154_1155insTTGTC

ype allele

50 75 100 125 150 175 200

(A)

(B)

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p.K385fs*47 (Type 2)

N domain

P domain

50 75 100 125

Size (nt)

C domain

Normal

150 175 200

c.1092_1143del

(Type 1)

KDEL

c.1092_1143del

p.L367fs*46 (Type 1)

50 75 100 125 150 175 200

Figure7.5 Detection of CALR exon 9mutations. (A) CALR mutations lie within the C- terminal portion of the CALR protein. (B) Detection of CALR exon 9mutations by fluorescent polymerase chain reaction followed by high- resolution capillary electrophoresis.

or biallelic DNMT3a mutations are found in between 7% and 10% of MPN patients and between 7% and 20% of MPN patients display mutations in TET2, with a higher incidence in advanced phase disease. IDH1/2 mutation “KI” mice models showed higher HSC proliferation, anemia, and extramedullary disease. Mutations such as ASXL1 and IDH1/2 in MF associate with worse outcomes, including shorter OS and increased rates of progression to blast- phase disease.

Mutations in spliceosome components SRSF2, U2AF1, SF3B1, and ZRSR2 are also more commonly observed in MF and in MDS/MPN crossover syndromes, with dysplastic changes seen on marrow morphology, including the ring

c.1154_1155insTTGTC

(Type 2)

Wild-t

Mutant allele

sideroblasts typically associated with the SF3B1 mutation, than in PV or ET where they are relatively rare. These mutations also confer a reduced OS in MPN and increased risk of AML evolution. Cell signaling genes affecting the RAS pathway (NRAS and SETBP1) and STAT 5 signaling (CBL) are associated with reduced OS, increased proliferation and may confer resistance to JAK inhibitors such as ruxolitinib as highlighted above. Genes affecting transcription and tumor suppression (e.g. TP53, RUNX 1, NF1, and NFE2) are associated with an increased risk of progression to AML from chronic phase disease and reduce survival in the blast phase. The presence of a low VAF TP53 mutation is common in thechronic

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phase of MPN; however, loss of heterozygosity ofthe wildtype allele through chromosomal deletion or uniparental disomy results in a rapidly expanding clone, which drives disease progression and leukemic transformation. Blast phase disease in this context is associated with a dismal prognosis.

Dynamic Clonal assessment (i.e. following the mutational profile over time) has shown that some mutations, e.g. TET2, as well as SF3B1 and DNMT3A more often precede acquisition of a JAK2 V617F mutation. These mutations are associated with clonal hematopoiesis, suggesting an “asymptomatic antecedent clone” predisposing to the MPN. These can be seen in the same colony expressing the JAK2 mutation (suggesting linear clonal evolution) or less commonly in a separate clone (suggesting biclonality). Mutations in ASXL1, EZH2, can occur before, contemporaneously or after, JAK2 mutations and IDH1 mutations are normally acquired after JAK2 V617F. CALR mutation is generally the earliest acquired in CALR- mutated MPN. Of interest, the order in which mutations are acquired in MPN may in fact correlate with clinical phenotype and possibly also response to treatment. In the example of concurrent TET2 and JAK2 mutation, as compared with patients in whom the TET2 mutation was acquired first, patients who acquired the JAK2 V617F mutation before TET2 mutations are often younger, have a greater likelihood of presenting with PV than with ET, an increased risk of thrombosis, and an increased sensitivity of JAK2- mutant progenitors to ruxolitinib in vitro. When a DNMT3A or TET2 mutation is acquired prior to JAK2 V617F, this associates with an ET phenotype.

Reticulin deposition in MPN

The presence/grade of reticulin deposition, or indeed its absence, are key components of the WHO diagnostic criteriaof MPNs. The WHO fibrosis grading system uses four grades (MF 0–3), although there can clearly be heterogeneous reticulin deposition. Primary MF requires characteristic megakaryocyte atypia or proliferation, accompanied by reticulin grade 2/3 and or collagen fibrosis, as a major requirement. The etiology of increasing reticulin deposition is complex and reliant on MPN-

associated hypercytokinemia, including PDGF and transforming growth factor (TGF) beta, and a disrupted HSC– mesenchymal stem cell– stromal microenvironment niche. The effects of novel agents on the grade and extent of reticulin deposition are under much review.

Chronic neutrophilic leukemia

CNL is a rare, often aggressive MPN defined by persistent mature neutrophilic leukocytosis, bone marrow granulocyte hyperplasia, and frequent hepatosplenomegaly (Table7.3). A seminal study published in 2013 described mutations in colony- stimulating factor 3 receptor (CSF3R) mutation as

Table7.3 Diagnostic criteria forCNL

CNL WHO 2022 diagnostic criteria

1. PB WBC ≥25 × 109/L

Segmented neutrophils plus band forms ≥80% of WBCs Neutrophil precursors (promyelocytes, myelocytes, and metamyelocytes) <10% of WBC Myeloblasts rarely observed Monocyte count <1 × 109/L No dysgranulopoiesis

2. Hypercellular BM Neutrophil granulocytes increased in percentage and number Neutrophil maturation appears normal Myeloblasts <5% of nucleated cells

3. Not meeting WHO criteria for BCR- ABL1+ CML, PV, ET, or PMF

4. No rearrangement of PDGFRA, PDGFRB, or FGFR1, or PCM1- JAK2

5. Presence of CSF3R T618I or other activating CSF3R mutation or In the absence of a CSFR3R mutation, persistent neutrophilia (at least 3mo), splenomegaly, and no identifiable cause of reactive neutrophilia, including the absence of a plasma cell neoplasm or, if present, demonstration of clonality of myeloid cells by cytogenetic or molecular studies.

WHO 2022 diagnostic criteria for CNL.

the oncogenic driver mutation in 89% of a cohort of CNL patients. This provided fresh insights into the molecular pathogenesis of CNL and led to the addition of molecular annotation to the WHO diagnostic criteria of CNL. This requires an absence of platelet- derived growth factor receptor (PDGFR) alpha, PDGFR beta, or FGFR1, or PCM1- JAK2 rearrangements and WHO criteria for BCR- ABL1

CML, PV, ET, or PMF and the presence of CSF3R T618I or other activating CSF3R mutation. Patients not meeting these criteria must exhibit specific clinical features and markers of clonality in order to attain the diagnosis.

CSF3R is involved in mitotic and maturation signaling, and regulates proliferation through downstream pathways involving JAK, STAT, RAS/RAF/MAP, SYK PI3K/Akt, and SRC kinases. The most common CSF3R mutations (in around 75%) are point mutations in T618I and T615a. These membrane- proximal mutations prevent o- glycosylation of the CSF3 receptor causing increased dimeric configuration, leading to ligand- independent receptor activation, and constitutive downstream signaling through JAK2. Such cases of CNL may display sensitivity to treatments with JAK2 inhibitors such as ruxolitinib. Frameshift or nonsense mutations leading to premature truncation of the cytoplasmic tailof CSF3R (D771fs, S783 fs, Y752X, and W791Z) are also seen (in around 25%), largely as compound mutations with membrane proximal or transmembrane CSF3R mutations.

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Receptor truncation mutations cause a loss of inhibitory regulatory mechanisms, including receptor internalization, and downregulation of binding sites for SOCS3, which targets the receptor for degradation. The relative scarcity of truncation only CSF3R mutations in CNL suggests that they, in isolation, are unlikely to be sufficient to cause CNL, and this theory has been supported in KI murine models. Truncation mutations may be resistant to JAK2 inhibition but are often sensitive to inhibition with the SRC kinase inhibitor dasatinib. Of note, ∼10–20% of CNL cases are negative for CSF3R T618I and other membrane- proximal mutations, suggesting that additional genetic lesions contribute to the leukemic phenotype in CNL.

The most common concurrent mutations found in CNL are ASXL1, SETBP1, SRSF2, TET2, and EZH2. Mutations in both JAK2 and CALR have also having been reported. SETBP1 mutation is seen most commonly in association with CSF3R mutations, when it promotes hematopoietic cell expansion through the upregulation of Myc- associated gene expression programs, promoting self- renewal of CSF3R- mutated hematopoietic progenitors and preventing terminal differentiation. The involvement of mutations also implicated in clonal hematopoiesis suggests CHIP may function as a possible backdrop to the later development of a CSF3R mutation. In this regard, studies have suggested that EZH2, SETBP1, TET2, U2AF1, and SF3B1 appear to be early mutations, while ASXL1, SRSF2, CSF3R, CBL, and NRAS, display a wider range of allelic frequencies and occur irregularly either in the founder clone or in later sub- clones.

Chronic eosinophilic leukemia andother eosinophilic disorders

Chronic eosinophilia leukemia (CEL), myeloid or lymphoid neoplasms associated with eosinophilia and idiopathic hypereosinophilic syndrome are rare diagnoses, which require careful exclusion of reactive causes of eosinophilia, and evaluation of clonality (Table7.4). In recognition of the growing list of recurrent, molecularly-

defined primary eosinophilias resulting from fusion tyrosine kinase genes, the major category “Myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1 or with PCM1- JAK2” (MLN- Eo) has been defined, with the latter fusion, PCM1- JAK2, added as a provisional entity in the 2016WHO categorization.

The FIP1L1- PDGFRA fusion gene occurs as a result of cytogenetically occult 800- kb deletion on 4q12, which can be detected by reverse transcription (RT)- PCR or fluorescence in situ hybridization (FISH) with a probe for the CHIC2 gene, which is located in the deleted segment. This fusion gene in association with an MPN with prominent eosinophilia is sufficient to diagnose “MPN with eosinophilia

Table7.4 CEL NOS

CEL NOS WHO 2017 diagnostic criteria

1. PB Eosinophil count ≥1.5 × 109/L

2. Absence of BCR- ABL1, PDGFRA, PDGFRB, or FGFR1

rearrangements and PCM1- JAK2, ETV6- JAK2, or BCR- JAK2

3. Not meeting criteria for CML, aCML, PV, ET, PMF, CNL, CMML, or AML

4. Myeloblasts >2% peripheral blood or 5–19% in the bone marrow or

5. Presence of clonal cytogenetic abnormality, including trisomy 8, (10;11)(p14;q21), and t(7;12)(q11;p11)

associated with FIP1L1- PDGFRA.” It is the most commonly identified genetic aberration in CEL and is often associated with increased peripheral blood mast cell tryptase levels, with increased numbers of loosely clustered mast cells in the marrow, in contrast to systemic mastocytosis, which is characterized by dense mast cell aggregates, and classically the cKIT D816V mutation.

Fusion genes involving PDGFRA, PDGFRB, or FGFR1 aretypical of clonal eosinophilia, and are often identified onkaryotyping, with the specific fusion partner gene being confirmed with FISH. In contrast to patients with the

FIP1L1-

PDGFRA fusion, those with PDGFRB or FGFR1

rearrangements can present without eosinophilia. Rarely, PDGFRB rearrangements are cytogenetically cryptic but can be detected by RT- PCR or RNAseq analysis. PDGFRB rearrangement is rare (<1%) but important if identified, given itsresponsiveness to imatinib, with the potential to achieve complete molecular remissions in such patients. CEL with FGFR1 rearrangement follows an aggressive course usually terminating in AML or T- acute lymphoblastic leukemia within 1–2 years. Imatinib is considered a definitive treatment for PDGFRA/B- re- arranged neoplasms with eosinophilia. Patients lacking evidence of the fusion genes mentioned above may attract a diagnosis of CELNOS, which requires molecular and/or morphological evidence of an eosinophilic myeloid malignancy, and a clonal cytogenetic or molecular marker, or >2% blasts in blood or >5% blasts in bone marrow.

Integration ofmolecular information into diagnostic algorithms andprognostication

Increasing integration of MPN molecular annotation into both diagnostic algorithms and prognostic scores has occurred as our knowledge of the molecular landscape has expanded over the last two decades. By way of example, this can be observed in

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the WHO and BSH MF, ET, and PV simplified diagnostic criteria (Tables7.1 and7.2, respectively), where molecular information makes the diagnostic criteria much more straightforward for practicing clinicians. Another good example is the heterogenous etiology of clonal eosinophilia, where increasing delineation of causative fusion genes facilitates much easier classification and ultimately therapeutic approaches, e.g. imatinib therapy for PDGFRA/B re- arranged neoplasms with eosinophilia. Multiple prognostic scores exist across the MPN spectrum, in particular for MF, and increasingly integrate molecular details to refine prognostication. Both the MutationEnhanced International Prognostic Scoring System 70 (MIPSS70) and MIPSS70 + v2.0 integrate clinicopathological, hematological, cytogenetic, and molecular information into one comprehensive score. MIPSS70 + V2.0incorporates not only the presence or absence of so- called high molecular risk (HMR) mutations (pathogenetic mutations in ASXL1, EZH2, SRSF2, IDH1/2, and U2AF1) but also takes into account the number. The MYSEC- PM score, for post PV- and post ET- MF, incorporates non- CALR mutation driver status alongside blast %, age, hemoglobin, platelets, and presence or absence of constitutional status. For ET, the international prognostic score of thrombosis in WHO- defined ET (IPSET- thrombosis) model incorporates JAK2 V617F mutation (associated with a higher risk of thrombosis) as one of the prognostic risk factors. The personalized prognosis calculator for MPN patients (https://cancer.sanger.ac.uk/mpn- multistage), was derived from PV, ET, and MF patient information and integrates 63 variables: demographic, clinicopathological, cytogenetic, and molecular information and allows for personalized outcome prediction. This can predict not only survival but also estimate the risk of blast phase transformation.

Conclusions

Molecular annotation across the MPN spectrum has led to clinically useful classification and diagnostic algorithms, led to rationale diagnostic approaches dependent on phenotype, frequently imparts relevant prognostic information, and has increased our ability to personalize therapeutic approaches for some. Increased understanding of the complex proand anti- apoptotic pathways underlying MPN initiation and propagation has led to the development of many novel agents targeting these pathways. The development of JAK inhibitors revolutionized the treatment pathway of MF. Ruxolitinib was the first approved JAK1/JAK2 inhibitor following the pivotal results from the two large international phase III trials COMFORT- 1 and COMFORT- 2. Since then, we have observed approval of both fedratinib pacritinib and momelotinib (in the United States) for MF and will hopefully soon see the availability of momelotinib elsewhere globally. Other agents in development for MF include BET inhibitors (Pelabresib) and

survival

BCL- 2inhibitors (navitoclax), either used as monotherapy or in combination with a JAK inhibitor. More information on how the molecular landscape determines response to these new agents paralleled with how these agents may modify, at least in part, aspects of the mutational profile is required.

One of the major remaining challenges in MPN management is accurately predicting transformation events– either when ET or PV transforms to post- ET MF and post- PV MF, respectively, or when chronic phase disease moves into accelerated or blast phase disease. Disparate clinicopathological and molecular features can aid prediction only in part and the unknown risks induce significant anxiety in both clinicians and patients. A clear predictive signal is lacking– this is a current focus in global MPN translational studies and most likely future modeling should incorporate not only clinical and genomic factors but in addition immunological and proteomic characteristics to accurately model disease trajectories and highlight the best timing and choice of therapeutic intervention.

Further reading

Introduction

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Levine, R.L., Wadleigh, M., Cools, J. etal. (2005). Activating mutation

in the tyrosine kinase JAK2in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 7 (4): 387–397.

Michiels, J.J., Berneman, Z., Schroyens, W. etal. (2015). Changing con-

cepts of diagnostic criteria of myeloproliferative disorders and the molecular etiology and classification of myeloproliferative neoplasms: from Dameshek 1950 to Vainchenker 2005 and beyond. Acta Haematol. 133 (1): 36–51.

The JAK2 V617F mutation in Philadelphianegative MPNs

Cross, N.C.P., Godfrey, A.L., and Cargo, C. (2021). A British Society

for Haematology good practice paper. The use of genetic tests to diagnose and manage patients with myeloproliferative and myeloproliferative/myelodysplastic neoplasms, and related disorders. Br. J. Haematol. 195 (3): 338–351.

Harrison, C.N., Butt, N., Campbell, P. etal. (2014). Modification of

British Committee for Standards in Haematology diagnostic criteria for essential thrombocythaemia. Br. J. Haematol. 167 (3): 421–423.

Khoury, J.D., Solary, E., Abla, O. etal. (2022). The 5th edition of the

World Health Organization classification of Haematolymphoid Tumours: myeloid and histiocytic/dendritic neoplasms. Leukemia 36 (7): 1703–1719.

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Myeloproliferative neoplasms 111

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McMullin, M.F., Harrison, C.N., Ali, S. etal. (2019). A guideline for

the diagnosis and management of polycythaemia vera. A British Society for Haematology guideline. Br. J. Haematol. 184 (2): 176–191.

Reilly, J.T., McMullin, M.F., Beer, P.A. et al. (2012). Guideline for the

diagnosis and management of myelofibrosis. Br. J. Haematol. 158 (4): 453–471.

JAK2 exon12mutations

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phologic features in polycythemia Vera with JAK2 exon 12mutations. Am. J. Clin. Pathol. 133 (6): 942–948.

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Germline JAK2 mutations

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V617I mutation in a family with hereditary thrombocytosis. Blood 118 (21): 1738–1738.

JAK2 germline haplotype

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(46/1) haplotype in myeloproliferative neoplasms: causal or random? Int. J. Mol. Sci. 19 (4): 1152.

Tefferi, A., Lasho, T.L., Mudireddy, M. etal. (2019). The germline JAK2

GGCC (46/1) haplotype and survival among 414 molecularlyannotated patients with primary myelofibrosis. Am. J. Hematol. 94 (3): 299–305.

Vannucchi, A.M. and Guglielmelli, P. (2019). The JAK2 46/1 ( GGCC )

MPN-

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MPL mutations in ET and MF

Alshemmari, S.H., Rajan, R., and Emadi, A. (2016). Molecular

pathogenesis and clinical significance of driver mutations in primary myelofibrosis: a review. Med. Princ. Pract. Int. J. Kuwait Univ. Health Sci. Cent. 25 (6): 501–509.

Guglielmelli, P. and Calabresi, L. (2021). The MPL mutation. Int. Rev.

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CALR mutations in ET and MF

Araki, M. and Komatsu, N. (2020). The role of calreticulin mutations in

myeloproliferative neoplasms. Int. J. Hematol. 111 (2): 200–205.

Holmström, M.O., Riley, C.H., Svane, I.M. etal. (2016). The CALR exon

9 mutations are shared neoantigens in patients with CALR mutant chronic myeloproliferative neoplasms. Leukemia 30 (12): 2413–2416.

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mutated or triple- negative myelofibrosis: clinical, cytogenetic

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28-

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negative

Chronic neutrophilic leukemia

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enhanced international prognostic score system for transplantation- age patients with primary myelofibrosis. J. Clin. Oncol. 36 (4): 310–318.

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