MYELOPROLIFERATIVE NEOPLASMS

• Myeloproliferative neoplasms (MPNs)


  Clonal hematopoietic disorders caused by genetic mutations in the hematopoietic stem cells that result in expansion, excessive production, and accumulation of mature erythrocytes, granulocytes, and platelets
• MPNs


  • Each MPN is characterized by the clonal expansion of one or more myeloid cell lines, but one cell line dominates
  • MPNs have the propensity to transform into other MPNs or progress into acute leukemias
• Myeloproliferation


  Largely due to hypersensitivity or independence of normal cytokine regulation resulting from genetic mutations that reduces cytokine levels through negative feedback systems normally induced by mature cells
• Hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) in MPNs


  Their fate is partially controlled by their interaction with the bone marrow stroma and the bone marrow microenvironment, including adhesion molecules, chemokines, chemokine receptors, and both soluble and membrane-bound factor receptors
• The three BCR-ABL1 negative primary MPNs may be preceded by or coexist with chronic inflammation, which may predispose to the development of other cancers
• Myeloproliferative neoplasms (MPNs)


  • Predominantly chronic with accelerated, subacute, or acute phases
  • In certain patients it is difficult to make a clear delineation between subacute and chronic phases using clinical and morphologic findings
• MPNs classified by the World Health Organization (WHO)


  • Chronic myeloid leukemia (CML)
  • Polycythemia vera (PV)
  • Essential (primary) thrombocythemia (ET)
  • Primary myelofibrosis (PMF)
  • Chronic neutrophilic leukemia (CNL)
  • Chronic eosinophilic leukemia, not otherwise specified (CEL-NOS)
  • Myeloproliferative neoplasm, unclassified (MPN-U)
• Primary myelofibrosis (PMF)


  Further subdivided into PMF, prefibrotic/early stage and PMF, overt fibrotic stage
• ET, PV, and PMF

  Genetically related based on the presence of the Janus kinase 2 (JAK2) mutation in most cases and the absence of the Philadelphia chromosome (Ph) or BCR-ABL1 fusion gene in all cases
• ET, PV, and PMF

  • Each present with proliferation of one primary myeloid element: thrombocytosis in ET, erythrocytosis in PV, and neutrophilia, a left shift, and eventual fibrosis in PMF
• ET and PV


  Very closely related because they share several driver mutations
• Primary myelofibrosis (PMF)


  A combination of overproduction of hematopoietic cells and stimulation of fibroblast production leading to ineffective hematopoiesis with resultant peripheral blood cytopenias
• Chronic myeloid leukemia (CML)

  Characterized by neutrophilia, a significant left shift to include all stages of myeloid development, and the presence of the Ph translocation and/or the BCR-ABL1 fusion gene
• The critical changes from the original French-American-British (FAB) classification to the WHO classification system for the MPNs include: 1) Ph and/or the BCR-ABL1 fusion gene is required for a diagnosis of CML; 2) minimum BM blast count threshold to differentiate MPNs from ALs is reduced from 30% to 20%; and 3) eosinophil disorders have been reclassified
• Ph- and BCR-ABL1-negative cases with myelodysplastic and myeloproliferative features are included in the WHO myelodysplastic syndrome (MDS)/MPN group and called atypical CML (aCML)
• In the category of MPNs, few changes were made from the 2008 to the 2016 classification system. The major changes include integration of new mutations to distinguish subtypes, some distinct morphologic features, and the elimination of mastocytosis as a MPN subgroup
• Myeloproliferative neoplasms (MPNs)


  • Present as stable chronic disorders that may transform first to a subacute and then to an aggressive cellular growth phase, such as acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL)
  • They may manifest a depleted cellular phase, such as BM hypoplasia, or exhibit clinical symptoms and morphologic patterns characteristic of subacute disease followed by a more aggressive cellular expression
• Familial MPNs have been described in families in which two or more members are affected
• Chronic myeloid leukemia (CML)

  • An MPN arising from a single genetic translocation in a pluripotential HSC producing a clonal overproduction of the myeloid cell line, resulting in a preponderance of immature cells in the neutrophilic line
  • CML begins with a chronic clinical phase and, if untreated, progresses to an accelerated phase in 3 to 4 years and often terminates as an AL (blast crisis phase)
  • Progression to AL can be of the myeloid type (AML) or the lymphoid type (ALL)
• Clinical features of CML

  • Frequent infection, anemia, bleeding, and splenomegaly, all secondary to massive pathologic accumulation of myeloid progenitor cells in bone marrow, peripheral blood, and extramedullary tissues
  • Neutrophilia with all maturational stages present, basophilia, eosinophilia, and often thrombocytosis are noted in peripheral blood
• The clonal origin of hematopoietic cells in CML has been verified in studies of females heterozygous for glucose-6-phosphate dehydrogenase. Only one isoenzyme is active in affected cells, whereas two isoenzymes are active in nonaffected cells
• Incidence of CML


  • Occurs at all ages but is seen predominantly in those aged 46 to 53 years
  • Represents about 20% of all cases of leukemia, is slightly more common in men than in women, and carried a mortality rate of 1.5 per 100,000 per year in the era before the development of imatinib mesylate
• Symptoms associated with clinical onset of CML

  Usually of minimal intensity and include fatigue, decreased tolerance of exertion, anorexia, abdominal discomfort, weight loss, and symptomatic effects from splenic enlargement
• Philadelphia chromosome


  A unique chromosome present in proliferating HSCs and their progeny in CML and must be identified to confirm the diagnosis
• The cause of the Philadelphia chromosome formation is unknown, but it appears more often in populations exposed to ionizing radiation. In most patients a cause cannot be identified
• Appearance of the Philadelphia chromosome in donor cells after allogeneic BM transplantation indicates the possibility of a transmissible agent
• Philadelphia chromosome


  A reciprocal translocation between the long arms of chromosomes 9 and 22, resulting in a unique chimeric gene, BCR-ABL1
• BCR-ABL1 fusion protein


  A 210-kD BCR-ABL1 fusion protein (p210BCR-ABL1) that expresses enhanced tyrosine kinase activity from the ABL1 moiety compared with its natural enzymatic counterpart
• Molecular genetics of BCR-ABL1

  The t(9;22) translocation that produces the BCR-ABL1 chimeric gene has been identified in four primary molecular forms that produce three versions of the BCR-ABL1 chimeric protein: p190, p210, and p230
• Formation of BCR-ABL1 fusion gene

  1. The breakpoint consistently occurs 5' of the second exon of the ABL1 gene such that exons 2 to 11 are contributed to the BCR-ABL1 fusion gene

  2. The BCR1 gene on chromosome 22 has four breakpoint regions: major BCR, minor BCR, and micro BCR

  3. The four BCR breakpoint regions combine with exons 2 to 11 of the ABL1 gene to form four versions of the BCR-ABL1 chimeric gene
• Two most common BCR-ABL1 fusion genes

  Involve the major BCR and form the p210 BCR-ABL1 fusion protein
• Less common BCR-ABL1 fusion gene

  Involves the minor BCR and forms the p190 BCR-ABL1 fusion protein
• Least common BCR-ABL1 fusion gene

  Involves the micro BCR and forms the p230 BCR-ABL1 fusion protein
• BCR-ABL1 fusion protein


  Expresses enhanced tyrosine kinase activity compared to the normal ABL1 protein, leading to aberrant cell signaling and uncontrolled cell proliferation
• Minor BCR


  Fusion gene product
• Major BCR


  Two specific breakpoints account for the t(9;22) translocation involved in the development of CML
• Breakage in the BCR1 gene in the major BCR

  1. Contributes exons 1 to 13 or 1 to 14

  2. The ABL1 gene contributes exons 2 to 11
• Chimeric protein product


  p210 protein
• Breakage in the minor BCR

  1. Contributes only exon one from BCR1

  2. Joins with the same exons 2 to 11 of ABL1 to produce a p190 protein
• Micro BCR breakpoint


  1. Contributes exons 2 to 19 from BCR1

  2. Fuses with ABL1 exons 2 to 11, producing the p230 protein