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Hematological System

Myeloproliferative neoplasms (MPN)

Clonal hematopoietic stem cell disorders characterized by the proliferation of one or more myeloid lineages.

Clonal hematopoietic stem cell disorders characterized by the proliferation of one or more myeloid lineages.

MPN comprise a group of distinct entities with overlapping pathogenetic mechanisms, clinical and histologic features, and molecular mutational profiles. Despite their similarities, they exhibit important differences in disease course and overall survival.

  • May evolve into, myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML), although the myeloproliferative diseases, on the whole, have a much better prognosis than these conditions

History

In 1951, William Dameshek described the concept of ‘myeloproliferative disorders (MPDs)‘ by grouping together chronic myelogenous leukaemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF) and erythroleukemia; he reasoned that a self-perpetuating trilineage myeloproliferation underlined their pathogenesis. Pre-Dameshek luminaries who laid the foundation for this unifying concept include Bennett, Virchow, Heuck, Vaquez, Osler, Di Guglielmo and Epstein. In 1960, Nowell and Hungerford discovered the Philadelphia (Ph) chromosome in CML. In 1967, Fialkow and colleagues used X-linked polymorphisms to establish CML as a clonal stem cell disease. Also in 1967, the PV Study Group was summoned by Louis Wasserman to study the natural history of PV and conduct large-scale clinical trials. In 1972, Janet Rowley deciphered the Ph chromosome as a reciprocal translocation between chromosomes 9 and 22, thus paving the way for its subsequent characterization as an oncogenic BCR-ABL mutation. In 1996, Brian Druker discovered imatinib-a small molecule ABL inhibitor with exceptional therapeutic activity in CML. In 2005, a gain-of-function JAK2 mutation (JAK2V617F) was described in BCR-ABL-negative MPDs, raising the prospect of a CML-like treatment strategy in PV, ET and PMF. The current review considers these and other landmark events in the history of MPDs.

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William Dameshek (1900 – 1969) was an American hematologist. Trained at Harvard, he was the founder of Blood, the prime core clinical journal of hematology, in 1946. He is also credited with describing the concept of myeloproliferative diseases in 1951. In addition, he participated in the first studies of nitrogen mustard in various hematological malignancies, widely considered the first uses of chemotherapy in malignant diseases. Dr Dameshek was also the first one who described chronic lymphocytic leukemia (CLL), a common form of leukemia in adults.

Physiology

Hematopoiesis:

Hematopoietic pluripotent stem cells have self-renewal capability and give rise to either myeloid or the lymphoid lineage which further differentiates into various mature blood cells such as red blood cells (RBC), lymphocytes, granulocytes, megakaryocytes, and macrophages. The hematopoietic process is determined by the bone marrow environment, growth factors, and transcription factors.


Classification

World Health Organization (WHO) classification:

Depending on the presence or absence of BCR-ABL1 fusion gene
Overview of the MPNs
Overview of the MPNs | Fowlkes, S., Murray, C., Fulford, A., De Gelder, T., & Siddiq, N. (2018). Myeloproliferative neoplasms (MPNs) – Part 1: An overview of the diagnosis and treatment of the “classical” MPNs. Canadian oncology nursing journal = Revue canadienne de nursing oncologique, 28(4), 262–268. https://doi.org/10.5737/23688076284262268

Pathophysiology

Phenotypic driver mutations:

The cardinal and mutually exclusive mutations in MPNs occur in JAK2, CALR, or MPL, referred to herein as the “phenotypic drivers” because of their role in driving the myeloproliferative phenotype. All of these converge on JAK-STAT signaling
Mutations in JAK2, CALR, and MPL drive excessive myeloproliferation via constitutively active signaling downstream of JAK2
Mutations in JAK2, CALR, and MPL drive excessive myeloproliferation via constitutively active signaling downstream of JAK2: JAK2 associates with the cytoplasmic portion of a variety of receptors, such as those for erythropoietin (EPOR), thrombopoietin (MPL), and granulocyte/macrophage colony-stimulating factor (G-CSFR). JAK2 is also activated in response to additional cytokines (eg, growth hormone and IL-5) (not shown). (A) Mutant JAK2, shown in red, is constitutively active and leads to variable levels of erythroid, megakaryocytic, and, to a lesser degree, granulocytic proliferation and differentiation. It is unclear whether mutant JAK2 dimerizes with mutant or wild-type JAK2 with respect to the individual receptors. (B) Mutations in CALR and MPL result in aberrant activation of signaling downstream of the MPL receptor. Mutant CALR complexes with MPL in the ER. Both mutations in CALR and MPL result in receptor dimerization and activation of JAK2. MAPK/ERK, mitogen-activated protein kinases/extracellular signal-regulated kinases; PI3/AKT, phosphoinositide 3-kinase/serine/threonine kinase Akt; STAT, signal transducer and activator of transcription. | Nangalia, J., & Green, A. R. (2017). Myeloproliferative neoplasms: from origins to outcomes. Hematology. American Society of Hematology. Education Program, 2017(1), 470–479. https://doi.org/10.1182/asheducation-2017.1.470
Clinical presentation in chronic phase and relationship to phenotypic driver mutation
Clinical presentation in chronic phase and relationship to phenotypic driver mutation: PV and ET are modeled as a disease spectrum along a biological continuum where different genetic lesions skew the clinical phenotype from that of thrombocytosis to that of additional erythrocytosis (±leukocytosis). CALR mutations result in excessive MPL signaling, in a manner similar to that resulting from MPL mutations. JAK2 mutations signal downstream of multiple cell surface receptors, including MPL, and are thus associated with thrombocytosis but also erythrocytosis and leukocytosis. The exact nature of the phenotypic driver mutation, germline genetic background, and additional somatic mutations influence disease phenotype. *In the context of JAK2V617F, several factors modulate the balance between erythrocytosis and thrombocytosis, including sex, mutation homozygosity, and patient-specific factors such as erythropoietin (EPO) levels, renal function, and iron status. | Nangalia, J., & Green, A. R. (2017). Myeloproliferative neoplasms: from origins to outcomes. Hematology. American Society of Hematology. Education Program, 2017(1), 470–479. https://doi.org/10.1182/asheducation-2017.1.470

Presentation

Classical (BCR-ABL1-negative) MPNs::

Characteristics and clinical and molecular features of the classical MPNs
Characteristics and clinical and molecular features of the classical MPNs | Fowlkes, S., Murray, C.S., Fulford, A., De Gelder, T., & Siddiq, N. (2018). Myeloproliferative neoplasms (MPNs) – Part 1: An overview of the diagnosis and treatment of the “classical” MPNs. Canadian oncology nursing journal = Revue canadienne de nursing oncologique, 28 4, 262-268 .

Diagnosis

The diagnosis of MPNs is often challenging due to similarities in the pathogenesis and symptoms of MF, PV, and ET. The diagnosis is typically made by a hematologist who will generally order blood and molecular tests, as well as a bone marrow biopsy.

World Health Organization (WHO) 2016 criteria:

WHO diagnostic criteria for the classical MPNs were established to facilitate differential diagnosis in clinical practice
Simplified 2016 WHO diagnostic criteria for the classical MPNs
Simplified 2016 WHO diagnostic criteria for the classical MPNs | Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, Bloomfield, Vardiman JW. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391–2405.

Bone marrow biopsy:

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Histologic examples of polycythemia vera (PV), essential thrombocythemia (ET), and prefibrotic primary myelofibrosis (PMF). Morphologic findings from bone marrow biopsies in (A) PV; (B) ET; (C) prefibrotic PMF. The key diagnostic features are summarized in the bottom panel | Wong, W. J., & Pozdnyakova, O. (2019). Myeloproliferative neoplasms: Diagnostic workup of the cythemic patient. International Journal of Laboratory Hematology, 41(S1), 142–150. https://doi.org/10.1111/ijlh.13005

Management

Common treatments for MPNs and nursing strategies to monitor/manage their associated side effects
Common treatments for MPNs and nursing strategies to monitor/manage their associated side effects | Fowlkes, S., Murray, C.S., Fulford, A., De Gelder, T., & Siddiq, N. (2018). Myeloproliferative neoplasms (MPNs) – Part 1: An overview of the diagnosis and treatment of the “classical” MPNs. Canadian oncology nursing journal = Revue canadienne de nursing oncologique, 28 4, 262-268 .
Non-pharmacological strategies for the management of the common MPN-associated symptoms
Non-pharmacological strategies for the management of the common MPN-associated symptoms | Fowlkes, S., Murray, C.S., Fulford, A., De Gelder, T., & Siddiq, N. (2018). Myeloproliferative neoplasms (MPNs) – Part 2: A nursing guide to managing the symptom burden of MPNs. Canadian oncology nursing journal = Revue canadienne de nursing oncologique, 28 4, 276-281 .

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