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Jak II |
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Also known as: Jak II: Renegade (UK), Jak II: Hors-la-loi (FR), Jak and Daxter 2 (JP) Developer: Naughty Dog Publisher: Sony Computer Entertainment Platform: PlayStation 2 Released in JP: March 11, 2004 Released in US: October 14, 2003 Released in EU: October 17, 2003 Released in AU: October 15, 2003 This game has unused areas. This game has a prototype articleThis game has unused graphics. This game has unused music. This game has unused sounds. This game has unused text. This game has debugging material. This game has regional differences. This game has a prerelease article |
Jak II is the second game in the Jak and Daxter trilogy, featuring a newer, darker world and a more badass Jak.
- 2Unused Areas
- 8Regional Differences
Jak is back in another action-packed adventure, but he's not the same. In Jak II, experiments with Dark Eco gone wrong leave Jak with an uncontrollable dark side, and after two years in prison, Jak seeks vengeance. Accompanied by your trusty friend Daxter, unleash the dark powers on multiple enemies and witness amazing transformations. Jak II (known as Jak II: Renegade in Oceania and Europe) is an open world platform third-person shooter action-adventure video game developed by Naughty Dog and published by Sony Computer Entertainment for the PlayStation 2.It is the second game of the Jak and Daxter series and is the sequel to Jak and Daxter: The Precursor Legacy.It was followed by Jak 3 a year later.
Sub-Pages
Unused Dialogue |
Unused Areas
Sandover Village
A complete, explorable Sandover Village from Jak and Daxter: The Precursor Legacy is accessible with hacks or a glitch. The area is used for the game's opening cutscene, but contains unseen objects such as the Precursor Oracle and village houses with fully detailed interiors. There are no traces of the adjacent levels such as Sentinel Beach or the two islands. When playing the level, the bridge leading to Samos' hut and the water don't have collision.
In a number of places where Scout Fly boxes were located in The Precursor Legacy, there are Krimzon Guard crates containing dark eco droplets. This is due to boxes in The Precursor Legacy using the internal name 'crate', with the KG crates in Jak II using the same name.
Halfpipe
To do:
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halfpipe is the internal name for a test level which can be loaded and has its own checkpoint. It includes the following assets:
- A green eco cluster
- A metal head grunt
- Swinging poles
- Crates
- Precursor orbs
Attempting to reach certain points of the area will cause the game to crash as it tries to load assets from The Precursor Legacy which are not present in the files. Because of this, most of the present assets also cannot be seen, as they are too close to the missing ones. The missing assets are:
- Eco vents
- A yellow eco cluster
- A red eco cluster
- A blue eco cluster
- A power cell
(Source: Luminar - Discovery)
Unused Graphics
WOMAP.STR, which stores the game's maps, includes a placeholder map labelled 'Palcab', referencing the Haven Palace cable stage, which actually uses the Haven City map.
Most of the game's maps have two parts, the second of which only appears as the player explores the area. The second part of the maps for the Krimzon Fortress and the Landing Pad have Precursor text at the side which is never seen in gameplay. The text for the Krimzon Fortress reads 'FORTRESS', while the Landing Pad text reads 'LANDING AREA'.
DESCREEN.STR contains instructions and previews leftover from the game's demo releases:
Unused Music
Track | Comments |
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A file which contains similar music to the final boss battle theme from Jak and Daxter: The Precursor Legacy, with three variations. The file was originally in The Precursor Legacy where it was also unused. | |
A similar version to this theme was later used in Jak 3. | |
A theme similar to the 'Mission Failed' music. | |
The music for Haven Palace has a second, unused track. It can be manipulated into playing by activating the Krimzon Guard alarm system when inside a room with no music which leads to an area with the palace theme. This occurs because the guard pursuit theme is the second track of the Haven City theme, therefore the next music that plays will also be a second track. | |
A track that was not intended to play in the final version. It was used as a placeholder music for a long time, and you can still trigger it only because the developers did not remove all its triggers properly. |
(Source: Luminar - Discovery)
Debug Mode
To do: Describe the error messages in more detail. |
Debug mode can be accessed by entering the following button combinations. There are two parts to the full combination and if each part is entered correctly, a sound effect from the menu screens of the prototype demos will play. The mode can be turned off using the same combinations. The combinations don't always reliably work but have a better chance of working when entered in the pause menu.
- First part: while holding down L3 press (using the D-Pad, not the analog stick) Up, Up, Down, Down, Left, Right, Left, Right, ✕, ✕, ◻, O, ◻, O
- Second part: while holding down L3 press (using the D-Pad) O, ◻, O, ◻, ✕, ✕, Right, Left, Right, Left, Down, Down, Up, Up
Debug mode unlocks the following features when pressing specific button combinations:
- L1 + R1 + L2 + R2: Turns on free camera mode, while making Jak disappear. The mode is turned off by pressing the same buttons, however this often results in glitches unless it is turned off in the pause menu accessed with the Select button.
- R2 immediately after taking damage: Health will be restored. This also prevents instant death, such as with security drones.
- L2 + R2: Jak will levitate. While levitating, R2 makes Jak ascend and L2 makes him descend. It is turned off by pressing L1 or ✕.
- Holding down L2 + R2 inside the Titan suit: The suit will levitate, but will fall once the buttons are released. Levitation also works this way in the debug mode for Jak and Daxter: The Precursor Legacy.
- (using the D-Pad) Up + Left + Select: Restarts the game. If used in free camera mode, it instantly respawns all the level's objects and all inventory items are lost.
- L1 or R1 during a cutscene: Changes the speed of the scene whilst displaying text that shows the speed rate. Holding L1 slows it down while holding R1 speeds it up. Pressing ✕ restores the normal speed.
- ✕ during a cutscene: Pauses the scene and shows the text 'scene paused'
- L1 in a minigame: The game is automatically lost
- R1 in a minigame: The game is automatically won
- R2 while the game is paused with Select: The game unpauses for one frame then re-pauses
- L2 + R1 on the Start menu: Replaces the menu options with the following:
Normal function | Debug function | Description |
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Missions | Select Start | Allows any mission to be played from the beginning. Functions in the same way as 'Level Select' in the main menu. |
Show Map | Select Pre-Start | Allows any mission to be played from its introductory cutscene. |
High Scores | Select Kiosk-Start | A small number of missions are playable. |
Game Options | Scene Player Act 1 | Functions in the same way as 'Scene Player Act 1' in the main menu. |
Graphic Options | Scene Player Act 2 | Functions in the same way as 'Scene Player Act 2' in the main menu. |
Sound Options | Scene Player Act 3 | Functions in the same way as 'Scene Player Act 3' in the main menu. |
Secrets | Secrets | Shows the 'Secrets' menu from the main menu screen instead of the in-game pause screen. |
If a second controller is plugged in, it can be used for the following:
- Holding down R3: Displays debug text
- △: Toggles debug text
- L3 + ◻: Toggles debug text
- L3 + O: Toggles debug text
- L3 + ✕: Gives Jak 1000 skull gems and Precursor orbs. Unlocks all guns and Dark Jak powers and JET-Board.
- L3 + R1 during a cutscene: Toggles debug text
Debug mode also results in various error and warning messages appearing in the top-left screen such as 'outside of bsp'.
(Source: Jak and Daxter Technical Wiki)
Demo Title Screen
An unused checkpoint loads the introduction cutscene and title screen from the game's demo releases. Like in the demos, the introduction cannot be skipped. In the North American version, the title screen has three options: 'Pumping Station', 'Strip Mine' and 'Watch Trailer' (the same as the E3 demo disc) while the European and Australian versions only have the first two options (the same as the Official PlayStation Magazine demo disc). Selecting 'Pumping Station' or 'Strip Mine' will make the game crash while 'Watch Trailer' will load an area from the cutscene, but the game will be stuck in a limited free-camera mode and will immediately auto-save. Reloading the saved game will simply play the demo introduction again, therefore making the save file unplayable.
Europe/Australia |
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Unused Text
Text for a mission that was removed:
Regional Differences
Europe/Australia
- In the driving tutorial 'Press R2 to change hover zones' is changed to 'Press R2 to change driving heights'.
- The 'Landing Pad' area is renamed 'Caspad'.
- There is an option to select a video frequency of 50Hz or 60Hz.
- In the languages option, the American flag is replaced with the Union Flag for English.
Japan
- Civilians cannot be killed, though the alarm system will still be activated after two hits.
- By default, Jak does not have a goatee. It must be turned on using the secrets menu.
- The circle button must be used when selecting Japanese or Korean in the language menu, but for other languages the X button also works.
(Source: Sultra)
The Jak and Daxter series | |
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PlayStation 2 | The Precursor Legacy (Prototype) • Jak II (Prototypes) • Jak 3 (Prototypes) • Jak X: Combat Racing (Prototypes) • The Lost Frontier |
PlayStation Portable | Daxter (Prototype) • The Lost Frontier |
PlayStation Vita | Jak and Daxter Collection |
Retrieved from 'https://tcrf.net/index.php?title=Jak_II&oldid=703818'
MYELOPROLIFERATIVE DISORDERSThe myeloproliferative disorders (MPD) are a group of haematological conditions where there is a primary disorder at the level of the multi-potent haematopoietic stem cell leading to increased production in one or more blood cell types. The three main disorders in the group are polycythaemia vera (PV), essential thrombocythaemia (ET) and idiopathic myelofibrosis (IMF). PV is characterised by an increase in red cells, white cells and platelets and clinically a plethoric appearance, itch and splenomegaly.
The disease can be complicated by thromboembolic phenomena and haemorrhage and in the end stages can progress to myelofibrosis and acute leukaemia. ET is characterised by an increased platelet count. Clinically it is frequently asymptomatic but the thromboembolic events may lead to disease detection.
There is a small propensity to progress to myelofibrosis and acute leukaemia which may be influenced by the treatment modalities used. IMF is defined by a leukoerythroblastic blood picture, splenomegaly and bone marrow fibrosis. The blood picture includes anaemia, thrombocythaemia or thrombocytopenia and variable white cell counts. The disease frequently progresses inexorably to transfusion dependent anaemia, symptomatic splenomegaly and transformation to acute leukaemia.A number of different biological phenomena have been described in haematopoietic cells from PV patients and other MPDs, the majority of which involve dysregulation of key signalling mediators. The key molecular events in the pathogenesis of these disorders have been poorly defined to date, except in the case of Chronic Myeloid Leukaemia (CML) with the associated characteristic chromosomal translocation ‘the Philadelphia chromosome’ and associated rearranged gene BCR – ABL.PV progenitor cells have been shown to grow in the absence of added erythropoietin, so called endogenous erythroid colony (EEC) formation and to be hypersensitive to a variety of other cytokines including insulin-like growth factor-1. EEC formation however is not specific to PV and is also identified in other MPDs. Other properties include increased expression of the inhibitor of apoptosis Bcl-x L in the absence of Epo in PV erythroid cells suggesting that deregulated expression of Bcl-xL may contribute to the erythropoietin dependent survival of erythroid lineage cells in PV.
Expression of the thrombopoietin receptor, Mpl, by platelets and megakaryocytes from patients with PV has been shown to be reduced compared to normal controls. This again is not specific to PV however and can occur in other MPDs. RNA synthesis from the polycythaemia rubra vera 1 (PRV-1) gene has been found to be over expressed in PV granulocytes. Erythroid colonies from PV patients have been shown to contain a hyperactive membrane-associated tyrosine phosphatase PTP-MEG2, although the exact role in erythrogenesis requires further investigation.Under normal conditions binding of the Epo receptor by its ligand induces rapid phosphorylation of Akt and subsequent stimulation of survival pathways for erythroid colonies.
Erythroid cells derived from individuals with PV have been shown to demonstrate increased phosphorylation of Akt/PKb and also Glycogen synthase Kinase 3. This contributes to inherent survival properties of the erythroid cells. Microarray analysis has identified candidate genes involved in the pathophysiology of PV including the transcription factor NF-E2 (Nuclear Factor (Erythroid-derived 2)).
![Palace Palace](https://vignette.wikia.nocookie.net/videojuego/images/f/f8/Portada_jak_2.jpg/revision/latest?cb=20070502190630)
This has been shown to be over expressed in the bone marrow megakaryocytic, erythroid and myeloid precursors of PV subjects.Over 50 years ago Dameshek linked together the recognised disorders PV, chronic myeloid leukaemia and IMF and speculated on the common myelostimulatory factors. In the early 1970s chronic myeloid leukaemia was separated as a distinct clonal disorder defined by a single chromosomal and latterly gene rearrangement ( BCR/ABL). Until very recently the other MPDs continue to be separated and diagnosed on the basis of their clinical and laboratory findings. However, recent molecular findings in the JAK2 gene are common to all these disorders. Polycythaemia VeraEssential ThrombocythaemiaIdiopathic MyelofibrosisA1 Raised Red Cell mass (25% above mean predicted value) or Hct ≥ 0.6 males; ≥ 0.56 femalesA2 Absence of cause for secondary erythrocytosis1. Platelet Count 600 × 10 9/l.NECESSARY CRITERIAA) Diffuse Bone Marrow FibrosisB) Absence of Philadelphia Chromosome or BCR-ABL transcript in peripheral blood cells.A3 Palpable splenomegalyA4 Clonality marker i.e acquired abnormal marrow karyotype2. No evidence of overt polycythaemia/polycythaemia masked by co-existing Iron deficiencyOPTIONAL CRITERIA(i) Splenomegaly of any grade(ii) Anisopoikilocytosis with tear drop erythrocytesB1 Thrombocytosis (platelet count 400 × 10 9/l)B2 Neutrophil Leucocytosis (neutrophil count 10 × 10 9 in non smokers; 12.5 × 10 9 in smokers)3.
Absence of a Philadelphia chromosome(iii) Presence of circulating immature myeloid cells4. Absence of peripheral blood and/or marrow appearances of myelodysplasia or myelofibrosis(iv) Presence of circulating erythroblastsB3 Splenomegaly (demonstrated on isotope/ultrasound scanning)B4 Characteristic BFUE growth or reduced serum erythropoietin5. No known cause of reactive thrombocytosis.
JANUS KINASE 2The JAK2 gene was first cloned in 1989 and is a member of a family of four Janus kinases 1, 2 and 3 and tyrosine kinase 2.It was originally named ‘just another kinase’ but the protein group was renamed Janus kinases after the Roman God of gates and passages. These non receptor kinases have two similar ‘active’ and ‘inactive’ domains and this is reminiscent of the God Janus who had the ability to look simultaneously in two directions.Each JAK has an active tyrosine kinase domain, JAK homology 1(JH1), a catalytically inactive pseudokinase domain, JAK homology 2 (JH2), a SRC homology 2 domain (SH2), and an amino terminal FERM (4-point-1, Erzin, Radixin, Moesin) homology domain where binding to type 1 cytokine receptors takes place. The interactions of the JAK2 FERM domain also comprises a role in trafficking of the EPO receptor (EPOR) cytoplasmic domain to the cell surface. Under normal physiological circumstances when a ligand (for example erythropoietin) binds with a receptor a conformational change occurs ( see ). The JAK2 protein then makes contact with the cytoplasmic domain of the receptor where it catalyses tyrosine phosphorylation. This primarily leads to the recruitment of STAT (signal transducer and activator of transcription) molecules which are then phosphorylated, homodimerise and translocate to the nucleus where they act as transcription factors.
Tyrosine phosphorylation also modifies other key regulatory events involved in cytokine signalling pathways. Diagram illustrating Functional JAK STAT PathwayThis “JAK STAT” pathway appears to be ubiquitous amongst vertebrates. Following ligand binding the activated JAK2 protein catalyses tyrosine phosphorylation in the cytoplasmic domain of the receptor and also leads to phospharylation of the Signal Transducers and Activators of Transcription (STATS).Phosphorylation of STAT leads to dimerisation via conserved Src homology 2 (SH2) domains. Translocation of these dimers to the nucleus then occurs facilitated via Nucleoprotein Interactor 1 (NPI-1). Subsequent regulation of gene expression following interaction with DNA response elements occurs. This leads to a transcriptional response. There is also interaction with the RAS/MAPK, Pl-3 K and Akt downstream pathways.Under normal conditions the enhanced gene expression is under complex negative feedback mechanisms including amongst others the production of the negative regulator Suppressors of Cytokine Signalling (SOCS).The JH2 domain is a non catalytic pseudokinase and has several crucial regulatory functions.
It appears that in the absence of ligand binding it has autoinhibitory properties, most likely manifest by a JH2/JH1 interaction, and if an alteration in this area occurred dysregulation of this autoinhibition would result. It also appears that maximal JAK2 activity in response to cytokines requires an intact JH2 region.In a short period in early 2005 four different groups described an identical mutation in JAK2 V617F in large numbers of patients with MPDs. – Although all groups arrived at the same result they approached it by different methods. The Vainchenker group, who are acknowledged to have made the discovery first, approached it from the point of view of the underlying biology of the disease. They had previously observed that inhibitors of JAK2 and other kinases interfered with the erythropoietin independent differentiation in PV. Therefore they looked at potential mechanisms leading to the formation of EECs.Identifying JAK2 as a potential candidate gene, and aware of its role as an upstream signalling molecule directly linked to the erythropoietin receptor, they focussed attention on this tyrosine kinase. They discovered that down regulating JAK2 expression via the introduction of short interfering RNA led to a marked inhibition of EEC formation in individuals with PV.
This obviously alerted the investigators to the key role of JAK2 in the formation of EEC and prompted sequencing of the coding exons and intron – exon junctions of the gene in three patients with PV and in two normal controls. Two of the individuals with PV demonstrated the presence of the JAK2 V617F mutation. In a further, larger group of patients with PV the mutation was present in 88% of cases. In all of the controls, in addition to all 35 samples of patients diagnosed with a secondary erythrocytosis, only wild type JAK2 was detected. Diagram of JAK2 Domains highlighting main roles and indicating approximate location of V617F Mutation.The mutation was shown to be acquired, as it was present in the myeloid lineage but absent in T cells. This group also identified the ability of the mutated JAK2 to spontaneously activate downstream STAT mediated transcription in the absence of the ligand erythropoietin.
This is in contrast to the inability of wildtype JAK2 to mediate such events. There was also activation of the ERK/MAP kinase and P13K/AKT pathways in the absence of alternative cytokine stimulation. In conclusion, the auto-inhibitory activity of JAK2 was disrupted by the presence of this V617F mutation.Skoda's group followed on from previous work where they had identified loss of heterozygosity (LOH) on the short arm of chromosome 9 in a proportion of MPD patients via genome wide microsatellite screening. This suggested that 9p may harbour a pathogenic mutation.
They initally utilised 10 microsatellite markers covering chromosme 9p and found 9p LOH in granulocytes derived from patients with MPDs in 21% (51/244) of cases and in no control cases, including CML. All 51 patients with 9p LOH possessed the JAK2 V617F mutation. Further investigation found the mutation in 65% of patients with PV of whom 27% had an acquired homozygous mutation and 38% a heterozygous mutation.Dysregulation of key tyrosine kinases is paramount to the pathogenesis of many cancers, including CML. This prompted further in depth searches for mutations in tyrosine kinases in the conventional myeloproliferative disorders. Gilliland's group undertook a search for mutations of tyrosine kinases using high-throughput sequence analysis and found the JAK2 V61F mutation. As part of a large study looking at protein kinase genes in MPDs, Green's group found the mutation in 57% of individuals with ET, 50% of individuals with IMF and 97% of those with PV.
It was detected in both granulocyte-macrophage and erythroid colonies and intriguingly was present in all EECs, demonstrating a link with growth factor hypersensitivity.The JAK2 V61F mutation accounts for some of the abnormalities described in PV although the molecular events linking the mutation with the biological parameters require further delineation. The JH2 domain is a pseudokinase and possesses autoinhibitory properties which prevent receptor phosphorylation. From modelling studies, the highly conserved valine at position 617 is predicted to lie on the upper surface of the N-terminal lobe of the JH2 domain. Substituting the valine for a large phenlyalanine destabilises the fold of the domain. Therefore the presence of the mutation would lead to a JAK2 which is constitutively active.
Interestingly, in heterozygotes there appears to be competition between the wild-type and mutant genes.Haematopoietic stem cells from MPD patients are hypersensitive to a range of growth factors and use JAK2 for signalling. Observations suggest a disruption of signal transduction downstream of JAK2 including constitutive activation of STAT3, up-regulation of the anti-apoptotic protein Bcl-x L and increased AKT activity. Death receptor stimulated apoptotic pathways also appear disrupted in JAK2 V617F PV derived erythroblasts with deregulated expression of the short isoform of c-FLIP which fundamentally plays an essential role in the normal homeostatic apoptotic cascade. DETECTION METHODSThe JAK2 V617F mutation in MPDs can be detected by a variety of methods. The simplest method is to isolate DNA from whole blood leukocytes and use PCR-direct sequencing. However, since the mutation is acquired and restricted to the myeloid lineage this method has a sensitivity of between 20 to 30%.
By implication the JAK2 V617F mutant clone would have to constitute a significant proportion of the total leukocyte population to be detectable by this method.Ficoll gradient centrifugation can be used to isolate mononuclear cells, with subsequent separation into granulocyte/macrophage lineages and lymphocytes. Methods to ensure an absence of gross contamination of the fractions should be utilised, for example magnetic sorting/flow cytometry. Isolation of DNA from the fractions can then occur and direct sequencing methods instituted. This allows detection of an acquired JAK2 V617F mutation in cells of myeloid lineage.Amplification Refractory Mutation Screening (ARMS) PCR permits a single base change to be detected under ideal PCR conditions. This is ideal for detection of the single base G → T transversion associated with the JAK2 mutation in question. The ARMS-PCR technique uses 4 primers as follows; a forward outer primer, a reverse outer primer, a forward inner wild type specific primer and a reverse inner mutant specific primer.
The forward primer from one set and the reverse from the other are able to amplify a positive control band. The other two primers span the site of the JAK2 V617F mutation. Therefore in the presence of the JAK2 mutation the reverse inner mutant specific primer and the forward outer primer bind to give a fragment of 279 bp.
In the presence of wild-type JAK2 the reverse outer primer and the forward inner wild-type specific primer produce a fragment of 229bp. Performing a dilution series indicates the level of sensitivity of ARMS-PCR to be 1-2%. The assay allows discrimination between homozygous and heterozygous individuals with the JAK2 V617F mutation and has a key role in acting as a reliable screening test for the presence or absence of the mutation in individuals with MPDs. CLINICAL CORRELATESOther groups have proceeded to look at their series of patients and identified similar rates of the presence of the mutation in the various disease groups. –, – Of interest is that the mutation is found extremely rarely in those with no identified cause of erythrocytosis and screening is therefore of benefit for the detection of clonal disease. The presence of the JAK2 V617F mutation has been correlated with other described biological phenomena such as PRV1 expression and EEC formation.
Patients who are JAK2 V617F mutation heterozygous or homozygous have been shown to express higher levels of NF-E2 compared to mutation negative individuals. PV: polycythemia vera, ET: essential thrombocythemia, IMF: idiopathic myelofibrosis, SM: systmemic mastocytosis, CNL: chronic neutrophilic leukemia, HES: hypereosinophilic syndrome, UN: unclassified MPD, MDS: myelodysplastic syndrome, CMML: chronic myelomonocytic leukemia.Those who are homozygous for the mutation may have different or more advanced disease compared to those who are heterozygous. Kravolics showed that those who were homozygous had a longer duration of disease and were more likely to develop secondary myelofibrosis. Tefferi demonstrated that in PV those possessing the homozygous JAK2 mutation tended to have higher haemoglobin levels, an increased incidence of pruritis and higher rates of fibrotic complications.The significance of considering cases with a very small percentage of JAK2 mutant positive clones as being “truly” JAK2 V617F positive remains unclear. Obviously one needs to consider what ‘cut off’ value we use to distinguish those possessing the mutation from those classified as mutation negative.
This is of importance if the presence of the JAK2 V61F mutation is to become paramount within the classification system of MPDs. Familial MPDs, including polycythaemia, have been well documented and it appears that even in these rare cases, the JAK2 mutation appears to be somatic rather than germ-line in nature.The impact of the mutation in IMF, from a clinical stance, appears somewhat less well defined. In a large study of myelofibrosis, Campbell et al showed that patients with the JAK2 V617F mutation had higher neutrophil and white cell counts compared to patients without the mutation and overall tended to have a poorer prognosis. Tefferi et al looked for the mutation in a variety of patients with myelofibrosis and found that the mutation was more likely to be present in patients with a previous history of PV compared to de novo MF.
The presence of the JAK2 V617F mutation in this fairly large cohort of 157 patients did not appear to have prognostic significance.The MRC-PT-1 prospective study of ET allowed comparison of mutation positive and negative patients. Those with the mutation had features resembling PV, higher haemoglobin, higher neutrophil counts, more venous thrombosis and a higher rate of transformation to PV but they had lower serum erythropoietin levels and ferritin levels. JAK2 V617F positive patients appeared to more sensitive to treatment with hydroxycarbamide but not anagrelide. Another series of ET patients showed that those with the mutation were more likely to transform to PV. These findings call into question the separation of the diseases PV and ET.
There may be a continuum of disease with the effects of the JAK2 V617F mutation on clinical presentation influenced by other modifiers including iron supply, erythropoietin suppression and other genetic modifiers ( see ). OTHER DISEASESThe presence of the mutation has been investigated in atypical MPDs including systemic mastocytosis, hypereosinophilic syndrome, chronic neutrophilic leukaemia, unclassified myeloproliferative disorders.
Of interest, McLornan et al detected the mutation in one chronic neutrophilic leukaemia patient with an unusual protracted course where the mutation may in some way influence the course of the disease. The mutation has been found in varying proportions of patients as summarised in.
It has been detected rarely in patients with myelodysplastic disorders. The prevalence of the mutation is higher in patients with acute myeloid leukaemia (AML) with antecedent PV or IMF than in the overall cohort. It has been reported rarely in other series of patients with AML and no patients with lymphoid leukaemia. FURTHER QUESTIONSThe fascinating discovery of a single mutation in a wide spectrum of MPDs has lead to rapid progress in the investigation of MPDs but leads to a number of further questions. The hierarchical position of this mutation requires further study. It is still not clear whether the JAK2 V61F mutation is the primary initiating event or a secondary event with an as yet unknown primary event.
While the presence of the mutation was sufficient to induce erythrocytosis in mice this is a manipulated experimental situation and it may not be sufficient to initiate disease in the human.Classification of MPD needs revision. The presence of the mutation demonstrates a clonal disorder but splitting of diseases on the basis of clinical characteristics needs reconsideration. Questions remain about the underlying pathogenesis in those with mutation negative myeloproliferative disorders. In summary, the discovery of a single mutation JAK2 V61F in a large number of MPD patients has lead to great progress in the understanding of MPDs but leads to many more exciting biological questions.
![](/uploads/1/2/7/4/127403874/484664252.jpg)