Sandbox: patho3

Pathogenesis

• Hairy cell leukemia arises from B cells, that are normally involved in the process of human immunoglobulins production.
• However, the exact B cell maturation stage involved in the development of hairy cell leukemia is still unclear.
• Hairy cell leukemia may also infiltrate the spleen and liver.
• Extravascular hemolysis may develop due to splenic sequestration and destruction of circulating red blood cells.
• Hairy cell leukemia does not infiltrate peripheral lymph nodes.
• Bone marrow failure may develop among hairy cell leukemia patients due to:

• Malignant cells infiltrateion of the bone marrow
• Reticulin fibrosis of the bone marrow
• Dysregulated cytokine production

• The development of bone marrow failure interferes with the normal production of red blood cells and platelets among hairy cell leukemia patients.
• Production of cytokines, such as TNF α and IL-2R, provide important stimuli for malignant B cells proliferation in hairy cell leukemia.
• As TNF α upregulates inhibitors of apoptosis such as IAP1 and IAP2, leukemic cells will demonstrate a prolonged survival due to the escape of apoptosis.
• In approximately 40% of hairy cell leukemia cases, malignant cells co-express multiple colonally related IgG, IgA, and IgM isotypes.

HCL is a slowly proliferating tumour expressing the apoptosis inhibitor BCL2

Mitogen activated protein kinases (MAPKs) have an important function in regulating HCL growth

The p38-MAPK–JNK cascade is inhibited

the MEK–ERK cascade is activated by protein kinase C (PKC) and SRC, which are constitutively active in HCL cells.

HCL is a slowly proliferating tumour expressing the apoptosis inhibitor BCL2, and escape from apoptosis is thought to be the main determinant of leukaemic-clone expansion. Mitogen activated protein kinases (MAPKs) have an important function in regulating HCL growth, with the p38-MAPK–JNK cascade transmitting apoptotic signals and the MAPK kinase (MAP2K, also known as MEK)–extracellular signal-regulated kinase (ERK) cascade conveying survival and cytoprotective signals. The p38-MAPK–JNK cascade is inhibited whereas the MEK–ERK cascade is activated by protein kinase C (PKC) and SRC, which are constitutively active in HCL cells. Expression of the HCL marker CD11c is also dependent on the ERK-induced activation of AP1/JUND. The autocrine-loop tumour necrosis factor (TNF)–TNF receptor 1 (TNFR1)contributes to the escape of HCL cells from apoptosis by upregulating the inhibitors of apoptosis IAP1 and 2 (possibly through nuclear factor B (NFB) activation), in a process that requires adhesion to the extracellular matrix (not shown). Despite their slow proliferation rate, HCL cells upregulate cyclin D1 and downregulate the cyclin-dependent kinase inhibitor p27. This feature might be caused by the activation of the phosphatidylinositol 3 kinase (PI3K)–AKT cascade, which could also transduce survival signals (including the inhibition of pro-apoptotic BCL2-antagonist of cell death (BAD)). Possible candidates for upstream activators of the PKC–MEK–ERK and PI3K–AKT pathways are represented by cytokines and growth factors that are present in the stromal microenvironment (FLT3L and interleukin 3 (IL3)) or autocrinely produced by leukaemic cells (basic fibroblast growth factor (bFGF)). In fact, HCL cells, upregulate all of the receptors for these ligands (FLT3, IL3, fibroblast growth factor receptor 1 (FGFR1)), as well as the bFGF co-receptors (CD44v3 and syndecan-3 (SYND3)). FGFR1 can be transcriptionally induced by cyclin D1 expression through phosphorylation of the retinoblastoma protein (pRB) and E2F activation. In leukaemic cells, bFGF also accumulates in the nucleus, where it can indirectly induce pro-survival genes. Genes that are specifically overexpressed in HCL cells (compared with normal B cells and with other B-cell lymphomas) are shown in red. Broken arrows represent activation or inhibition events, the occurrence of which, although well described in non-HCL cells, has not been formally investigated in HCL cells.

Genetics

• The most common gene involved in the pathogenesis of hairy cell leukemia is BRAF V600E mutations.
• The BRAF V600E mutations is present in all patients with hairy cell leukemia (classic).
• The BRAF V600E mutations is not present in patients with hairy cell leukemia (variant).
• Other genes involved in the pathogenesis of hairy cell leukemia may include:

• Under expression of chromosomes 3p24, 3p21, 3q13.3-q22, 4p16, 11q23, 14q22-q24, 15q21-q22, 15q24-q25, and 17q22-q24.
• Over expression of chromosomes 13q31 and Xq13.3-q21