Myeloproliferative Neoplasms (MPNs)

Myeloproliferative Neoplasms (MPNs) Defined

• MPNs are clonal hematopoietic disorders caused by genetic mutations in hematopoietic stem cells (HSCs).
• These mutations lead to the expansion, excessive production, and accumulation of mature blood cells.
• Each MPN has a clonal expansion of one or more myeloid cell lines.
• MPNs can transform into other MPNs or progress to acute leukemias (ALs).
• Myeloproliferation occurs due to hypersensitivity or independence of normal cytokine regulation.
• HSCs and hematopoietic progenitor cells (HPCs) interactions with bone marrow stroma influence MPNs.
• BCR-ABL1 negative primary MPNs could be preceded by or coexist with chronic inflammation.
• MPNs are mainly chronic, and certain patients cannot make a boundary between subacute and chronic phases.
• Cellular expansion happens in different areas of the body.
• Classified by the WHO into chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia, not otherwise specified (CEL-NOS) and MPN, unclassified (MPN-U).
• ET, PV, and PMF are genetically linked by the Janus kinase 2 (JAK2) mutation and the off the absence of the Philadelphia chromosome or BCR-ABL1.
• PV presents with a proliferation of erythrocytosis, ET presents with a proliferation of thrombocytosis, and PMF presents with neutrophilia.
• PMF consists of stimulation and overproduction of hematopoietic resulting in stimulating ineffective fibroblast production.

Chronic Myeloid Leukemia (CML)

• Characterized by neutrophilia, and a left shift.
• Includes the Ph translocation and/or the BCR-ABL1 fusion gene.
• MPNs minimum BM blast count threshold to differentiate MPNs from ALs has been reduced to 20%.
• Eosinophil disorders have been reclassified.
• MPNs major changes include integration of new mutations, distinct morphologic features and the elimination of mastocytosis as a subgroup.
• MPNs present with an aggressive growth phase, cellular phase such as BM hypoplasia or exhibit patterns of subacute disease.
• Familial MPNs have impacted multiple family members.

CML Genetic Translocation

• CML arises from a single genetic translocation that has predominance of immature cells in the neutrophils.
• Progresses to an AL, blast crisis, or accelerated phase if untreated.
• Common clinical features are infection, anemia, bleeding, and splenomegaly.
• Patients experience Neutrophilia, thrombocytosis, basophilia, and eosinophilia
• Only one glucose-6-phosphate dehydrogenase isoenzyme is active in the affected cells.

CML Incidence rate, Symptons

• Primarily affects those aged 46 to 53 years and represents about 20% of all cases of leukemia.
• Mortality rate of 1.5 per 100,000 per year before imatinib mesylate was developed which is a tyrosine kinase inhibitor that has changed the outcome.
• Common clinical symptoms include: fatigue, anorexia, abdominal discomfort, decreased tolerance of exertion, splenic enlargement and weight loss, fatigue.

Cytogenetics of the Philadelphia Chromosome

• Philadelphia chromosome is present in HSCs and their progeny in CML.
• Indicates the possibility of a transmissible gent if appearance of Ph in donor cells occurs after BM.
• CML discovered in 1960, reciprocal translocation in 1973.
• Specifically reflects the translocation of q34 of proto-oncogene from Chromosome9 to q11of chromosome22.
• Produces a 210-kD BCR-ABL1 fusion protein that exerts enriched tyrosine kinase activity from the ABL1 moiety.

Molecular Genetics

• This translocation has 4 primary forms with 3 different proteins.
• Occurs BCR exons vary in the region chromosome to chromosome 9.
• Four BCR genes: BCR1, BCR2, BCR3, BCR4.
• The BCR1 gene is involved in the Philadelphia translocation.

Pathogenetic Mechanism

• The wild-type codes for the protein which has normal tyrosine kinase.
• The protein expresses threonine, serine kinase activity, and has protein kinases function.
• If protein kinases occur ABL1 must be first before phosporylated.
• SH3 is the domain of the phosphorilation.
• Activation cascades or signaling pathways are designed to activate certain genes for cells.
• In CML BCR-ABL1 translocation occurs and the kinases can not be shut-off, because losing it results in constitutive tyrosine .

Leukocytes and Bone Marrow

Other Labratory Findings

• Hyperuricemia and uricosuria can be associated with secondary gout, urinary uric acid stones, and kidney.
• Approximately 15% exhibit total white blood cell greater than a 109/L.
• Symptoms are vascular stasis and possible intravascular consumption of oxygen by the leukocytes of lowering the total blood count.
• In discussed blood findings diagnosis can be confirmed by t(9;22) , genetic hybridization, or polymerase for the fusion transcript.
• It has been shown that it is useful to diagnose CML.

Progression

• Most dieases will transfer into Blastic transformation
• Those patients proceed throughout meta phases, poor responses and bad lab values. Additional abnormalites affect that show enhanced dyshematopoiesis.
• Can effect more abnormalies to create more blastic cells of AL that exhibits increased blasts.

Releated Diseases

• Those that are clinicallt similiar to CML but is Phelladilphia chromosone or express only a few cels, CNL expresses with many similar pattern to CML that effects Neutrophilic Granulates
• In JML, the number of monocytes and granulocytes cause anemia
• Sometimes, Ph is found in the Paitents of CML with more mutations

Treatment

• Early treatments for CML inclued alkylating agents such as busulfan
• Improved out comes improved the suppressions of the Philadelphia , reduce progressoion
• BM more effective with a transplant of BM
• In some patients the infusion after BM is helpful for remisons
• Iminitib a synthetic protiens that bounds BCL-ABL1 more.
• Goals of therapy include the absencse of ph chromosomes.
• Complete remission of pathway
• The treatment is measured by BL transcripts is most measured test
  • Those with lower blood are can effect the hemilogic count
  • The limitation is the resistence of imimitib
  • Resitence comes in the following forms
  • primay loss for the ability to recah recission -Seconday- 42 nonths loing Two casues accquitions mutations expression of point mutations of ATP

Myeloproliferative Neoplasms Treatment Continued

• High doses of Imatinib mesylate are indicated if the primary dose is inadequate.
• Dasatinib, nilotinib, and bosutininb all work as alternate forms of BCR-ABL1 resistant mutants, other ABL1 proteins.
• Ponatinib all four FDA drugs are resistant this mutations, and has 42-43 A loop
• 3rd generation - This requires other processes to have function protein activity
• The effectiveness is homa haring that is not 3-1

Polycythemia Vera (PV)

• It is an MPN and results in erythroctyes. granulocytes and platelets are all heightened.
• Splenomegaly is a common occurence. It happens in a HSC and is clonal by nature.
• The rare incident of PV varies from contry to Japan and the United States, mostly occurs after and occurs more in white, jewish men and woman.
• Some cells are hypersensitve, and some is dependent on the growth of erythropoietin and this the grwoth happens.
• Results are linked to this and this can lead to a new understanding of JAK2.

PV Continued

• JAK2 mutation is associated to the cytokine proteins and runs near the cell membrane.
• When a protein is activated it gets activated.
• JH2 1 domain with control and JH are different and may affect kinase activity.
• JAK2 V617F (95%) of patients.
• Causes a change resulting with amino and binding which has to do with conformoational change, converting it to active.
• JAK2 can also bind to several factors. These protein affect and drives cells.

Types of Myeloproliferative Neoplasms

• In these cases the MPL, the mutation suggest there will be a hyper mutative
• JAK2 mutatuin will suggest that the MPL, 2 proteins exists which converts the epo disease
• The additional may evolve due to fibrosis. Because it appears almost in PV has been known what that other mutations have been found.

Stimulus of Erythropoiesis

• All things and features that relates to V617f

Peripheral Blood and Bone Marrow in chronic phase CML

• BM in those that are there that
• Some patients express that BM more express the features of the other in myclodesia, those with what the pattern of myeloid with features that classification.

Diagnosis for Polythemia Vera

• The diagnosis needs the WHO standard what shows that the factors
• Primary is pre-primary myelofibrious, with what is more associated with both the BM and its characteristics.
• Chronic neuphrilic leukemia is a more rare disorder.
• Those that are affected show more features of the cells.

Clinical Presentation for Polycythemia Vera

• PV has mild symptoms.
• The blood is with RCM producing. The stages occurs before this , all the processes happen, the
• PV produces patients a high risk for thrombotic

Summary of cont, of PV

Treatment and Prognosis

• The PV the stages involves phlbotony with modern .
• Ruxoliin binds the 1 which helps with certain features.

What the next steps

• The following cases may be affected:
• JAK2 most mutations

Essential Thrombocythemia

• Clonal MPN with increased megakaryopoiesis and thrombocytosis, the normal count is 400.

Additional Notes contd.

• More common for women than men, and typically occures at ages 30s and up to 60s
• As of this, what makes these diseases is what gives the diseases those certain characteristics is the , MPL, and another type of mutation that that causes
• It what the patient can see to help that or with with something

Myeloproliferative Neoplasms (MPNs) are clonal hematopoietic disorders. They are caused by genetic mutations in hematopoietic stem cells (HSCs), leading to the expansion and accumulation of mature blood cells. MPNs can transform into other MPNs or progress to acute leukemias.