Overview: Oncology – Liquid Tumors (Hematological Malignancies)
Hematological malignancies, such as leukemia and lymphoma, are cancers that affect the blood, bone marrow, and lymph nodes. In recent years, the incidence of hematological malignancies has steadily increased in the United States (U.S.) and is expected to account for 10 percent of new cancer cases diagnosed in the U.S. in 2019.1
The Wnt pathway is a primary physiological regulator and signaling pathway that controls the activity of stem cells. These specialized cells have the unique ability to self-renew and form multiple cell types and tissues.2 Hematopoiesis is the process in which stem cells develop into mature blood cell components. The Wnt signaling pathway has been shown to have an effect on controlling the proliferation, survival, and differentiation of hematopoietic cells.3 Altered expression or activity of various Wnt pathway components through DNA mutations or epigenetic changes (without gene mutation) in stem or normal cells can cause Wnt signaling to be inappropriately activated, resulting in transformation, proliferation, and replicative immortality of cells.2,4 Therefore, this pathway, which is normally tightly regulated, can become hijacked in malignant tumors and contribute to cancer development and progression.2,4,5 As evidence of this, aberration of Wnt pathway proteins is detected in many hematological cancer patients.6 Therefore, modulation of the Wnt pathway with small-molecule drugs offers a potential therapeutic option for the treatment of hematological malignancies.
Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Risk factors include advanced age, genetic disorders, and smoking and high exposure to radiation, chemotherapy, or toxic chemicals.7
- There will be an estimated 21,450 newly diagnosed U.S. cases of AML in 2019, mostly in adults.8
- AML will be responsible for an estimated 10,920 U.S. deaths in 2019, almost all in adults.8
- For adults who are 20 years of age and older, the five-year relative survival rate is 24%.9
Wnt signaling pathway activation has been implicated in AML development and progression.10-13
- Studies have shown that β-catenin, a proto-oncogene and key component of the Wnt signaling pathway, is overexpressed in the blood cells of more than half of patients diagnosed with AML compared to individuals without AML.10,11
- Multiple studies have shown that epigenetic alterations resulting in the inactivation of Wnt signaling pathway inhibitors contribute to AML.12,13
Mantle Cell Lymphoma (MCL) is a less common form of non-Hodgkin B-cell lymphoma that is frequently aggressive and incurable. MCL occurs more often in men than it does in women.14 Though the exact cause of MCL is unknown, people are usually diagnosed in their 60s.14
- Each year, there are an estimated 4,300 new cases of MCL in the U.S.15
- The median overall survival of individuals with MCL is 4 to 5 years after diagnosis.16
Evidence suggests that the Wnt signaling pathway is involved in the development of MCL.17,18
- Activated Wnt signaling has been found in MCL and appears to promote tumor cell growth.17
- In vitro pharmacological inhibition of Wnt signaling was effective at eliminating a subpopulation of MCL-initiating cells implicated in MCL resistance to chemotherapy.18
Diffuse large B-cell lymphoma (DLBCL) is an aggressive type of non‐Hodgkin lymphoma (NHL). DLBCL is the most commonly diagnosed type of NHL worldwide and represents approximately 22% of new NHL cases in the U.S. each year.19,20 Potential risk factors for DLBCL include underlying illnesses or medications that lead to immunosuppression, ultraviolet radiation, pesticides, certain hair dyes, and diet.21
- Each year, more than an estimated 18,000 individuals are diagnosed with DLBCL in the U.S.22
- The five-year relative survival rate for DLBCL is approximately 63%.23
Substantial evidence suggests that Wnt signaling pathway alterations contribute to DLBCL tumorgenicity.24-26
- Dual expression of the anti-apoptotic protein BCL-2 and MYC, a Wnt target gene27, was predictive of poor survival in DLBCL patients.24,25
- Wnt signaling pathway mutations were demonstrated in primary DLBCL tumor samples.26
- https://www.lls.org/http%3A/llsorg.prod.acquia-sites.com/facts-and-statistics/facts-and-statistics-overview/facts-and-statistics_Accessed on August 7, 2019.
- Clevers H & Nusse R. Wnt/β-catenin signaling and disease. Cell. 2012;149(8):1192-1205
- Reya T, Duncan AW, Ailles L, et al. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature. 2003;423:409-14.
- Hanahan D & Weinberg R. Hallmarks of cacer: the next generation. Cell. 2011;144(5):646-7
- de Sousa EM, Vermeulen L, Richel D, Medema JP. Targeting Wnt signaling in colon cancer stem cells. Clin Cancer Res. 2011;17(4):647-53.
- Reviewed in: Graiger S, Traver D, Willert K. Wnt Signaling in Hematological Malignancies. Prog Mol Biol Transl Sci. 2018;153:321-41.
- https://www.cancer.org/cancer/acute-myeloid-leukemia. Accessed on August 7, 2019.
- https://www.cancer.org/cancer/acute-myeloid-leukemia/about/key-statistics.html Accessed on August 7, 2019.
- American Cancer Society. Cancer Facts & Figures 201 Atlanta: American Cancer Society; 2019.
- Serinsöz E, Neusch M, Büsche G, et al. Aberrant expression of beta-catenin discriminates acute myeloid leukaemia from acute lymphoblastic leukaemia. Br J Haematol. 2004;126(3):313-9.
- Ysebaert L, Chicanne G, Demur C, et al. Expression of beta-catenin by acute myeloid leukemia cells predicts enhanced clonogenic capacities and poor prognosis. Leukemia. 2006;20(7):1211-6.
- Griffith EA, Gore SD, Hooker C, et al. Acute myeloid leukemia is characterized by Wnt pathway inhibitor promoter hypermethylation. Leuk Lymphoma. 2010;51(9)1711-9.
- Valencia A, Román-Gómez J, Cervera J, et al. Wnt signaling pathway is epigenetically regulated by methylation of Wnt antagonists in acute myeloid leukemia. Leukemia. 2009;23(9):1658-66.
- http: //www.cancer.ca/en/cancer-information/cancer-type/non-hodgkin-lymphoma/non-hodgkin-lymphoma/mantle-cell-lymphoma/?region=onhttps://www.reference.com/health/prognosis-mantle-cell-lymphoma-8c5efbc98f4278d0_Accessed on August 7, 2019.
- Vose JM. Mantle cell lymphoma: 2017 update on diagnosis, risk‐stratification, and clinical management. Am J Heamtol. 2017;92:806-13.
- Gelebart P, Anand M, Armanious H, et al. Constitutive activation of the Wnt canonical pathway in mantle cell lymphoma. Blood. 2008;112(13):5171-9.
- Mathur R, Sehgal L, Braun FK, et al. Targeting Wnt pathway in mantle cell lymphoma-initiating cells. J Hematol Oncol. 2015;8:63.
- Siegel R, Miller K, Jemal A. Cancer statistics, 20 CA Cancer J Clin. 2019; 69(1):7‐34.
- SEER. SEER Database: All Lymphoid Neoplasms with Detailed Non‐Hodgkin Lymphoma Subtypes; SEERb Incidence Rates and Annual Percent Change by Age at Diagnosis. NCI; 2002‐2011.
- Friedberg JW. Diffuse Large B-Cell Lymphoma. Hematol Oncol Clin North Am. (2008);22(5)941.
- https://www.lymphoma.org/aboutlymphoma/nhl/dlbcl/. Accessed on August 7, 2019.
- https://seer/cancer.gov/statfacts/html/dlbcl.html. Accessed on August 7, 2019.
- Scott D, Mottok A, Ennishi D, et al. Significance of Diffuse Large B-Cell Lymphoma Cell of Origin Determined by Digital Gene Expression in Formalin-Fixed Paraffin-Embedded Tissue Biopsies. J Clin Oncol. 2015;33(26):2848-56.
- Staiger AM, Ziepert M, Horn H, et al. Clinical Impact of the Cell-of-Origin Classification and the MYC/ BCL2 Dual Expresser Status in Diffuse Large B-Cell Lymphoma Treated Within Prospective Clinical Trials of the German High-Grade Non-Hodgkin's Lymphoma Study Group. J Clin Oncol. 2017;35(22):2515-26.
- Zhang J, Grubor V, Love CL, et al. Genetic heterogeneity of diffuse large B-cell lymphoma. Proc Natl Acad Sci USA. 2013;1110(4):1398-403.
- Herbst A, Jurinovic V, Krebs S, et al. Comprehensive analysis of beta-catenin target genes in colorectal carcinoma cell lines with deregulated Wnt/beta-catenin signaling. BMC Genomics. 2014;15:74.