Development of Leukemia and Lymphoma

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Leukemia is a disease of stem cells that arise in bone marrow. In contrast lymphoma cells tend to arise in peripheral tissues from mature cells1,2,3,4,7,8. Many lymphomas are derived from B cells in lymph node germinal centers, likely due to the active Ig gene rearrangements. Both result in clonal expansion of the cells involved and can lead to the bone marrow, blood, and secondary lymphoid organs being overwhelmed by malignant cells.

Leukemias can derive from any cell type or lineage in hematopoietic differentiation including erythroid, myeloid, and lymphoid, and specific cell types within each lineage such as B cell, T cell, or NK cell1,2,3,4,7,8. Acute leukemias such as Acute Lymphocytic Leukemia (ALL) and Acute Myeloid Leukemia (AML) tend to arise from less differentiated progenitors while chronic leukemias such as Chronic Lymphocytic Leukemia (CLL) and Chronic Myeloid Leukemia (CML), and lymphomas, have a more differentiated phenotype4.

Leukemic cells retain certain lineage and cell-type specific markers and morphology, surface molecule expression, and internal enzyme expression (e.g. TdT)1,3,7. For example, T cell malignancies may express common T cell surface antigens such as CD2, CD3, and CD5, while B cell malignancies might express surface immunoglobulin, CD19, and/or CD20. Myeloid leukemic cells typically express some combination of the myeloid markers CD13, CD14, CD33, and CD64, while NK-derived neoplasms express CD561,3,7.

Many leukemias and lymphomas are associated with hallmark mutations, translocations, and epigenetic expression patterns. They can result from loss of function of tumor suppressor genes or aberrant oncogene activation and signaling2,9. Epigenetic factors include DNA methylation, histone acetylation, chromosome organization, and microRNAs5,8. The nature of the mutations has implications for prognosis and therapeutic options.

Among the most common mutations are tumor suppressors such as p53 and PTEN. Other common mutations are those resulting in constitutive activation of the BCR or TCR, inhibition of death mechanisms, or increased expression of survival factors. The chromosomal translocation t(9;22) (Philadelphia chromosome) is characteristic of CML and results in the activation of the BCR/ABL oncogene2,4,6. The translocation of Myc into the IgH or IgL locus is characteristic of many B cell neoplasms8. Epigenetic methylation patterns can be used to identify subtypes of AML5.

Every hematopoietic malignancy has a small population of self-renewing cells called leukemic stem cells (LSCs), similar to normal hematopoietic stem cells (HSCs)4,6. LSCs are mostly quiescent and therefore resistant to chemotherapy. They offer the transformed cells a mechanism for survival and can give rise to relapses following chemotherapy.

It is becoming clear that development of leukemias is not as linear as previously thought2. Instead, it is an evolutionary process influenced by the accumulation of multiple mutations. This process results in a heterogeneous transformed cell population. Natural selection and competition take place between leukemic stem cells and normal HSCs within the bone marrow or tumor microenvironment. Mutations or combinations of mutations that give LSCs and tumor cells a selective growth and survival advantage will ultimately become dominant in within the leukemic population2

 

Below is the current listing of Bethyl antibodies involved in MAPK signaling pathway research:

 

References

1. Borowitz MJ, Bray R, Gascoyne R, Melnick S, Parker JW, Picker L, Stetler-Stevenson M. 1997. U.S.-Canadian Consensus recommendations on the immunophenotypic analysis of hematologic neoplasia by flow cytometry: data analysis and interpretation. Cytometry 30(5):236-44. PMID: 9383097.

2. Ferrando AA, López-Otín C. 2017. Clonal evolution in leukemia. Nat Med. 23(10):1135-1145. PMID: 28985206.

3. Foon KA, Schroff RW, Gale RP. 1982. Surface markers on leukemia and lymphoma cells: recent advances. Blood 60(1):1-19. PMID: 6805534.

4. Misaghian N, Ligresti G, Steelman LS, Bertrand FE, Bäsecke J, Libra M, Nicoletti F, Stivala F, Milella M, Tafuri A, Cervello M, Martelli AM, McCubrey JA. 2009. Targeting the leukemic stem cell: the Holy Grail of leukemia therapy. Leukemia 23(1):25-42. PMID: 18800146.

5. Ntziachristos P, Abdel-Wahab O, Aifantis I. 2016. Emerging concepts of epigenetic dysregulation in hematological malignancies. Nat Immunol. 17(9):1016-24. PMID: 27478938.

6. Riether C, Schürch CM, Ochsenbein AF. 2015. Regulation of hematopoietic and leukemic stem cells by the immune system. Cell Death Differ. 22(2):187-98. PMID: 24992931.

7. Schroff RW, Foon KA, Billing RJ, Fahey JL. 1982. Immunologic classification of lymphocytic leukemias based on monoclonal antibody-defined cell surface antigens. Blood 59(2):207-15. PMID: 7034809.

8. Sun R, Medeiros LJ, Young KH. 2016. Diagnostic and predictive biomarkers for lymphoma diagnosis and treatment in the era of precision medicine. Mod Pathol. 29(10):1118-42. PMID: 27363492.

9. Younes A, Ansell S, Fowler N, Wilson W, de Vos S, Seymour J, Advani R, Forero A, Morschhauser F, Kersten MJ, Tobinai K, Zinzani PL, Zucca E, Abramson J, Vose J. 2017. The landscape of new drugs in lymphoma. Nat Rev Clin Oncol. 14(6):335-346. PMID: 28031560.