Chronic myelogenous leukemia pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: James Nasr[2]

Chronic myeloid leukemia (CML), a myeloproliferative disorder, which is characterized by the uncontrolled expansion of immature bone marrow cells of myeloid origin.The hallmark of CML is the formation of the Philadelphia chromosome resulting from the reciprocal translation (9;22)(q34;q11.2), resulting in a derivative 9q+ and a small 22q- ultimately forms a BCR/ABL fusion gene and production of a BCR/ABL fusion protein. The gene product of the BCR/ABL gene constitutively activates numerous downstream targets including c-myc, Akt and Jun, all of which cause uncontrolled proliferation and survival of CML cells.

• The circulating blood cells are produced in bone marrow after a series of events termed as hematopoiesis.^[1]
• The bone marrow has an tremendous regenerative ability; it is estimated that 10 trillion red blood cells and 80 to 90 trillion leukocytes are formed per hour at the basal rate.
• In addition to that, while cell numbers are maintained within narrow limits in normal subjects, they can be promptly increased when required.
• Bone marrow primarily has small percentage of pleuripotent stem cells which give rise to various progenitor cells.
• Hematopoeisis occurs in the vertebrae, pelvic bones, metaphysis of long bones such as femur, humerus in basal state.
• However, during certain stressful conditions that require rapid and massive hematopoiesis such as thalassemia it then returns to its former site, liver, spleen and sometimes lymph nodes.
• These hematopoietic stem cells (HSCs are multipotent and have the ability to differentiate into the cells of all 10 blood lineages:
  • Erythrocytes
  • Platelets
  • Neutrophils
  • Eosinophils
  • Basophils
  • Monocytes
  • T and B lymphocytes
  • Natural killer cells
  • Dendritic cells
• This differentiation is mediated through multiple growth factors and cytokines. ^{[2] [3]}
• The hematopoietic stem cells (HSCs) and progenitor cells are supported by a stromal cell network that provides cell-cell contact support.
• The stromal network provides two major functions:
• An adhesive framework onto which the developing cells are bound, these cells produce:
  • A variety of adhesion molecules.
  • Hematopoietic Growth factors or cytokines that are thought to support the survival, proliferation, and differentiation of HSCs and progenitors. ^[4]
• Primitive mesenchymal stromal cells (MSCs) are thought to have the capacity to differentiate into following:
  • Osteolineage cells
  • Chondrocytes
  • Adipocytes
  • Perivascular cells
• Overall Differentiation of myeloid progenitors is mediated through:^[5]
  • The production of essential hematopoietic growth factors.
  • Several signaling pathways have come up as integral control devices of HSC fate, such as:^[6]
    • Notch
    • Wingless-type (Wnt)
    • Sonic hedgehog (Shh)
    • Smad pathways
• These signaling circuits provide an important structure for our understanding of HSC regulation, alongwith providing information of how the bone marrow micro environment couples and integrates extrinsic with intrinsic factors responsible for HSC differentiation and development of chronic myeloid leukemia.^[7]

• Chronic myeloid leukemia (CML), a myeloproliferative neoplasm, characterized by the presence of the Philadelphia chromosome which is thought to be a definitive diagnostic marker for CML.^[8]
• In Philadelphia chromosome translocation, parts of two chromosomes (the 9^th and 22^nd by conventional karyotypic numbering) switch places.
• As a result, part of the BCR (“breakpoint cluster region”) gene from chromosome 22 is fused with the ABL (“abelson murine leukemia“) gene on chromosome 9.
• This abnormal “fusion” gene generates a protein of p210 .
• Because ABL carries a domain that can add phosphate groups to tyrosine residues (a tyrosine kinase), the BCR/ABL fusion gene product is also a tyrosine kinase.
• The fused BCR/ABL protein interacts with the interleukin 3 beta c receptor subunit.
• The BCR/ABL transcript is continuously active and does not require activation by other cellular messaging proteins that promotes growth and replication through downstream pathways such as:
  • RAS
  • RAF
  • JUN kinase
  • MYC
  • STAT
• In turn BCR/ABL triggers a cascade of proteins which control the cell cycle, speeding up cell division.
• Moreover the BCR/ABL protein inhibits DNA repair, causing genomic instability and making the cell more susceptible to developing further genetic mutations.
• The action of the BCR/ABL protein is the pathophysiologic cause of chronic myelogenous leukemia.^{[9][10][11][12][8][9]}

• Recent studies have demonstarated that BCR/ABL also stimulates the production of reactive oxygen species (ROS), which levels increase with CML progression and this in turn increases BCR/ABL self-mutagenesis.
• Tyrosine kinase inhibitor resistance can also be related to higher ROS production.
• Therefore, ROS-induced self-mutagenesis of BCR/ABL is of prime significance for CML progression.
• These can be dependent on DNA repair, which is modulated by BCR/ABL and can be different in CML stem and progenitor cells.^[13]

• Implication of altered bone marrow signalling on stem cell persistence in the bone marrow niche.
• Recent advancements have been trying to establish the relationship between bone marrow pathway and Wnt pathways and their role to alter the Cdx-Hox axi.^[14]

• CML cells present in contact with stroma or fibronectin continue to proliferate, suggesting that failure to adhere through integrin receptors may also underlie the abnormal proliferation of CML progenitors.^[15]
• Although, CML progenitors express the same integrin receptors as normal progenitors, they fail to adhere to stroma and fibronectin.
• This indicates that structural or functional abnormalities of these receptors can be integral part of pathogenesis.

• Chronic myeloid leukemia (CML) in blast crisis is the transition of CML in chronic or accelerated phase to an acute leukemia.
• It is characterized by:
  • ≥ 30% blasts in the bone marrow or peripheral blood.
  • The development of extramedullary disease outside of the spleen.
• In light of recent changes in the World Health Organization, definition of acute leukemia, the percentage of blasts required for CML in blastic phase may someday be reduced to 20%.^[16]
• Consistent with the early stem cell nature of CML, blastic transformation may be:
  • Myeloid
  • Lymphoid
  • Undifferentiated/mixed
• Myeloid blast crisis being about two times more common than lymphoid.

• It is suggested that blast crisis is due to one of following reasons:^[17]
  • BCR/ABL is considered to be responsible for progressive genomic instability or epigenetic changes, which occur at the CML stem cell level and/or in later CML progenitor cells.
  • The degree of genomic instability is directly related to the level of BCR/ABL kinase activity.
  • The third is that CML stem cells are the least vulnerable to ABL-targeted therapy and may serve as reservoirs for CML progression.

• All these events concomitantly result in the acquired loss of hematopoietic cell differentiation, resulting in a highly progressive generation of immature blasts in peripheral blood and in bone marrow.
• Various studies have BCR/ABL is implicated in the generation and maintenance of secondary DNA alterations.

• Following genetic changes have been observed which play crucial role in progression of disease phase.
  • Duplication of the Ph chromosome, trisomy 8, and isochromosome 17.^[18]
  • Alterations in p53 have been found in only a minority of cases.^[19]
  • Loss of p16INK4A/ARF has been reported in up to half of patients with CML in lymphoid blast crisis but is rare in the myeloid form.^[20]
  • Thus, it is hypothesized that clonal evolution plays integral role in blastic progression and is likely facilitated by the dysregulation of normal apoptotic pathways by BCR/ABL.

• Recent studies have implicated activation of the following pathways ^[21]
  • LYN
  • AKT
  • STAT5

• CML-CP is driven by the constitutively active BCR::ABL1 tyrosine kinase, resulting from the t(9;22)(q34;q11) translocation (Philadelphia chromosome).^[22]
• The abnormal BCR::ABL1 protein leads to continuous activation of tyrosine kinase signalling pathways, decreased apoptosis, inadequate cellular differentiation, and accumulation of granulocytic lineage cells. ^[23]
• In CML-CP, myeloproliferation predominates, and many patients are asymptomatic or present with mild symptoms related to anemia or splenomegaly.^[24]

• Accelerated-phase chronic myeloid leukemia (CML-AP) represents disease progression from the indolent chronic phase toward biologic instability and increased leukemic burden. ^[25]
• CML-AP is characterised by rising blast counts, increasing basophilia, worsening cytopenias, and the development of additional cytogenetic abnormalities.^[26]
• CML-AP is associated with decreased responsiveness to tyrosine kinase inhibitor (TKI) therapy and increased progression to blastic-phase CML (CML-BP).^[26]

• CML-BP is characterised by marked expansion of immature blasts in the peripheral blood or bone marrow and clinical deterioration. ^[26]
• Cytogenomic features of CML-CP are associated with disease progression, decreased responsiveness to TKI therapy, and progression to CML-BP. ^[27]

On gross pathology, no distinctive findings are seen in chronic myeloid leukemia.

Blast cells are seen on peripheral blood smear of patients of chronic myeloid leukemia which are present during blast crisis.

• 
  Blast crisis of chronic myelogenous leukemia (CML). Peripheral blood smear revealing the histopathologic features indicative of a blast crisis in the case of chronic myelogenous leukemia.^[28]

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