Leukemia refers to cancers of cells residing in the blood and bone marrow. The bone marrow is a fluid compartment within bones, in which blood cells develop and mature. When the most immature cells (stem cells) mature, they first differentiate into either myeloid or lymphoid cells. Myeloid cells eventually develop into either 1) mature red blood cells, which carry oxygen throughout the body 2) platelets, which help form clots to stop bleeding and 3) a type of white blood cell known as granulocytes, which fight infection and disease. Lymphoid cells, on the other hand, develop into 3 different kinds of mature white cells that also fight infection (B lymphocytes, T lymphocytes or natural killer cells).
While there are many different forms of leukemia, they can be separated into chronic leukemias and acute leukemias, based on the aggressiveness of the disease. Leukemias are also named after the kind of blood stem cell involved (myeloid or lymphoid). In acute myeloid leukemia (AML), the bone marrow produces cancerous white blood cells (called myeloblasts). These cancerous cells crowd the marrow and suppress normal development of red cells, white cells and platelets. The disease usually worsens quickly without treatment. In contrast to AML, acute lymphocytic leukemia (ALL) is a disease where the bone marrow produces too many cancerous lymphocytes (lymphoblasts). Similar to AML, they crowd the marrow and suppress the development of healthy blood cells. ALL usually progresses quickly and is lethal without treatment. In chronic myeloid leukemia (CML), cancerous myeloid cells are involved, but the disease progresses slowly.
For CML, the FDA has approved the use of effective targeted therapies, including dasatinib (Sprycel), imatinib (Gleevec) and nilotinib (Tasigna) for the treatment of patients with CML. These drugs inhibit an abnormal protein present in the malignant cells of CML, and are highly effective in controlling the disease. However, despite significant efforts, therapeutic advances in the field of acute leukemias are lagging. Therefore, novel drugs and therapeutic strategies are desperately needed.
Source: National Cancer Institute, 2013
Acute leukemias are aggressive hematologic malignancies that result from the dysregulation and proliferation of hematopoietic precursors that are arrested in differentiation. Acute myeloid leukemia (AML) is a malignancy of aberrant myeloid precursors and is associated with a poor prognosis. The estimated number of yearly deaths (10,370 people according to 2013 data) is nearly as many as the number of new diagnoses (14,950 people). While the majority of those with AML achieve a complete remission with traditional cytotoxic induction therapy, approximately half ultimately relapse. Outcomes are worse for those with relapsed or high-risk AML, such as those who are older or have preceding myelodysplastic or myeloproliferative conditions. Over the last thirty years, advances in supportive care and consolidation therapy have resulted in incrementally improved outcomes. However, long-term survival of patients diagnosed with AML continues to be poor.
The outcomes for acute lymphoid leukemia (ALL) have dramatically improved in the pediatric population over the last 30 years. Children with ALL traditionally undergo intensive treatment strategies, including multi-agent induction therapy, early intensification, multi-agent consolidation therapy, as well as intrathecal treatment with ongoing long-term maintenance therapies. ALL in adults is distinguished from that in children by a higher proportion of poor-risk chromosomal alterations (such as the Philadelphia chromosome), a lower proportion of good-risk alterations (such as the TEL-AML1 gene fusion) and a lower prevalence of the poor-risk T-cell phenotype. Additionally, adults tend to experience increased toxicities and decreased tolerance to the traditional and intensive pediatric multi-agent therapies. Historically, adults with ALL have a worse prognosis when compared to pediatric patients, with reported event free survival (EFS) rates of 30-40% in adults as opposed to >80% for pediatric populations. The outcome is particularly worse for relapsed disease. Therefore, as with AML, clinical investigation of novel agents with therapeutic promise is needed, particularly for treatment in the adult population.
Chronic myeloid leukemia (CML) is characterized by a novel fusion gene, BCR-ABL, typically arising from a reciprocal translocation between chromosomes 9 and 22, leading to a constitutively activated tyrosine kinase. Prior to the development of targeted tyrosine kinase inhibitor (TKI) therapy for this disease, survival was poor, with 5-year survival rates of approximately 40% in patients 20-44 years of age. Imatinib mesylate, a tyrosine kinase inhibitor with activity against the novel BCR-ABL gene product, revolutionized both the care of this disease and the approach to molecular targets in cancer therapies. Imatinib, along with other second generation TKIs, such as dasatinib, nilotinib, and bosutinib, now constitute the backbone of CML treatment. As a result, clinical outcomes for patients with CML have dramatically improved over the course of the past decade.
Source: National Cancer Institute, 2013
CLICK IMAGE FOR MORE INFORMATION
The IDH1 gene encodes an enzyme called isocitrate dehydrogenase 1, found in the compartment of cells called the cytoplasm. This enzyme is normally involved in the transfer of energy from one molecule to another during certain biochemical reactions within the cell.
Mutations involving the IDH1 gene have been found in various cancers, including Acute Myeloid Leukemia (AML), intrahepatic bile duct cancers (Cholangiomas), Chondrosarcomas, and specific brain tumors (gliomas and glioblastomas). These alterations cause the amino acid (protein building block) arginine to be replaced by a different amino acid at a key position in the long chain of amino acids that make up this protein. The change in amino acid sequence alters the structure of the protein, resulting in loss of its normal function. Instead of its' normal metabolic product, the mutated IDH1 produces a new metabolite, R (-)-2-hydroxyglutarate, also called 2-HG. 2HG inhibits Tet and KGM enzymes, which alter the organization of DNA and disrupt normal gene expression patterns. These changes contribute directly to the development of cancer.
Tumor mutation profiling performed clinically at the MGH Cancer Center has identified the highest incidence of IDH1 mutations in brain tumors called gliomas (50-60%) and glioblastomas (~10%), cholangiocarcinomas (18-25%), chondrosarcomas, and Acute Myeloid Leukemia (5-10%).
The IDH1 gene encodes for the metabolic enzyme isocitrate dehydrogenase 1. This enzyme is located in the cytoplasm and peroxisomes of cells, and normally functions to catalyze the oxidative decarboxylation of isocitrate to alpha-ketoglutarate, with the production of NADPH.
Recurrent mutations in IDH1 occur primarily at codon 132. These mutations result in decreased normal enzymatic activity, while conferring neomorphic activity that produces the oncometabolite R(-)-2-hydroxyglutarate (2HG) as the end-product. Levels of 2HG can accumulate dramatically in IDH1-mutant tumors and this is thought to promote tumorigenesis by competitively inhibiting the activity of a number of dioxygenases. The net effect appears to involve the promotion of gene silencing through hypermethylation of DNA and histones, as well as the activation of the hypoxia-inducible factor signaling pathway.
Tumor genotype testing performed clinically at the MGH Cancer Center has identified the highest incidence of IDH1 mutations in low-grade gliomas (50-60%), glioblastomas (~10%), cholangiocarcinomas (18-25%), chondrosarcomas, and acute myeloid leukemias (5-10%).
IDH1 mutations are more common in cases of acute myeloid leukemia which also display a NPM1 gene mutation, as well as those cases in which chromosomal analysis of leukemic cells are normal or considered intermediate-risk.
The novel enzymatic activity conferred by IDH1 gene mutations is believed to provide a desirable target for effective anti-cancer therapies. Indeed, agents that target mutant IDH activity are under active development and clinical study. A clinical trial studying an IDH1 inhibitor AG-120 is currently accruing patients at the MGH cancer center.
The high levels of the metabolite produced by mutant IDH activity in cancer cells (2-HG) can be detected in the blood and urine of IDH1-mutant acute myeloid leukemia patients. Monitoring the extent of reduction (associated with treatment response) or rise (associated with disease relapse) in 2-HG levels during chemotherapy may provide a non-invasive method of following treatment effects in IDH1-mutant-AML patients. There remains significant debate as to whether the presence of an IDH1 mutation in AML affects prognosis and outcomes among patients.
IDH1 mutations are more common in acute myeloid leukemias with a concurrent NPM1 gene mutation, and normal or intermediate-risk cytogenetics.
The novel enzymatic activity conferred by IDH1 gene mutations in cancer is believed to provide a robust target for therapeutic intervention. Novel therapies targeting mutant IDH1 activity are under active development and clinical study. A clinical trial of the IDH1 inhibitor,
AG-120, is currently accruing patients with AML and other myeloid malignancies at the MGH cancer center.
IDH1-mutant acute myeloid leukemia (AML) has been associated with a hypermethylation phenotype, and thus gene silencing in this disease, possibly mediated by the aberrantly produced oncometabolite, 2-hydroxyglutarate (2-HG). The high levels of 2-HG produced by mutant IDH activity in cancer cells, can also be detected in the blood and urine of patients with IDH1-mutant AML. Monitoring the extent of reduction (associated with treatment response) or increase (associated with disease relapse) in 2-HG levels during chemotherapy has been studied and may provide a non-invasive means of following disease activity in IDH1-mutant AML patients.
There remains significant debate as to whether the presence of an IDH1 mutation in AML affects prognosis in patients.
The mutation of a gene provides clinicians with a very detailed look at your cancer. Knowing this information could change the course of your care. To learn how you can find out more about genetic testing please visit http://www.massgeneral.org/cancer/news/faq.aspx
or contact the Cancer Center.