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Expand Collapse Leukemias  - General Description 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
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
PubMed ID's
10502596, 19959104, 19880497, 272207, 2943992, 11222362, 10749961, 17327603, 9716583, 18048644, 21327563, 12712476, 21576640, 22157290
Expand Collapse ATR  - General Description
CLICK IMAGE FOR MORE INFORMATION
The protein encoded by ATR is a serine/threonine kinase and DNA damage sensor, activating cell cycle checkpoint signaling and causing a pause in the cell cycle following DNA replication stress or damage. The activated protein can phosphorylate and activate several important proteins that are involved in the inhibition of DNA replication and cell division, which are critical for DNA repair.

The maintenance of intact, correctly sequenced DNA is vital to the life of a cell. If there are mistakes made in replicating DNA before cell division, subsequent daughter cells will have inaccurate or damaged DNA, and may either die or carry mutations that can contribute to the development of cancer. For this reason, cells have evolved multiple pathways to repair mistakes in-or damage to- DNA. The specific repair pathway used by the cell depends on the type of DNA damage that has occurred. The types of DNA repair that we are focusing on relate directly to cancer. These involve a break in BOTH strands of DNA, which can be the result of ionizing radiation or other DNA damaging agents. This type of DNA damage is called Double Strand Breaks (DSB's). There are two main pathways used by cells to repair DSB's in DNA, one is Homologous Recombination (HR), the other is Non-Homologous End Joining (NHEJ). This page of our website focuses on the HR pathway (there is a separate web page for NHEJ repair if you select PKcs from the gene list when you sign on to this page).

Many proteins are involved in the complex HR pathway to repair DSB's in DNA. There is a graphic above that depicts the HR pathway (if you click on the graphic, it will enlarge and become a bit easier to follow). While complicated, the DSB at the top right of the graphic is acted upon by a series of proteins in the circle of steps shown that ultimately lead to the complete and accurate repair of the DSB in the DNA.

Some of the proteins involved in the HR DSB repair pathway are MRE11, NBS1, RAD50. These three proteins make up the MRN complex. This complex detects DSB's in the DNA. Once the DSB is found by the MRN complex, the MRN complex functions with BRCA1 and CtIP to resect the DSB’s to form single stranded DNA “tails”. Meanwhile, DSB's also activate the ATM protein, which in turn acts upon CHK2 to activate it, as well as directly activating the tumor suppressor TP53. TP53 can cause cell cycle delay, giving the cell time to repair DNA breaks or mistakes before the cell cycle leading to division resumes. In the next step, RPA binds to the single stranded DNA "tails" that have been created by BRCA1 and CtIP in conjunction with the MRN. The binding of RPA activates another protein called ATR. ATR has many important functions, including activating CHK1, which can cause cell cycle delay giving cells time to repair DNA. ATR also regulates BRCA1 which recruits a bound group of proteins including PALB2/BRCA2/RAD51. In the next step, RAD51 displaces the RPA that is on the single stranded DNA, with the involvement of BRCA2/PALB2 and RAD51c. BRCA1/BARD1 helps RAD51 coated single stranded DNA invade double stranded DNA with homologous sequences to form a DNA repair loop. With the help of DNA polymerases, the repair loop creates the opportunity to use the intact homologous DNA as a template to correctly repair DSB’s. Enzymes called ligases reconnect the ends of the DNA, leading to complete and accurate repair of the DSB in DNA.

After studying familial cancer syndromes, germline or inherited BRCA1 and BRCA2 were identified a while ago as proteins that when altered by mutation, cause certain cancers. Some BRCA1 and BRCA2 genes become mutated somatically, meaning in a non-inherited way. When either gene is mutated, the resulting protein cannot perform its role in DNA repair correctly. This turns out to be true for other proteins in the HR pathway as well. Recently, scientists have found mutations in many of the other genes that encode the proteins involved in the HR pathway. Mutations in HR pathway members include MRE11, NBS1, RAD50, ATM, CHK2, BRCA1, PALB2, RAD51, BRCA2, BARD1, and RAD51c (these are depicted in red in the above graphic). This remarkable number of mutations in proteins involved in the DNA repair pathway found in cancer highlights how important the HR DSB DNA repair pathway is in cells. The mutations in HR pathway proteins result in proteins that do not function properly in their role in DNA repair. Without proper function of the proteins involved in DNA repair, DNA mistakes or breaks are not properly repaired, and the damaged DNA contributes to the development of cancer.

ATR is only rarely mutated in cancer, however, the frequent mutations in ATM result in cells that are completely reliant on the ATR pathway to repair DSB's in the DNA. This has therapeutic implications for treatment of tumors that have mutations in the HR DNA repair pathway.

Testing for mutations in the many genes/proteins involved in DNA repair discussed above is available in the MGH genetics lab. Treatment as well as clinical trials studying new drugs that target defects in these proteins-including ATR- are available at the MGH Cancer Center.

The protein encoded by ATR is a serine/threonine kinase and DNA damage sensor, activating cell cycle checkpoint signaling and causing a pause in the cell cycle following DNA replication stress or damage. The activated protein can phosphorylate and activate several important proteins that are involved in the inhibition of DNA replication and cell division, which are critical for DNA repair.

The maintenance of intact, correctly sequenced DNA is vital to the life of a cell. If there are mistakes made in replicating DNA before cell division, subsequent daughter cells will have inaccurate or damaged DNA, and may either die or carry mutations that can contribute to the development of cancer. For this reason, cells have evolved multiple pathways to repair mistakes in-or damage to- DNA. The specific repair pathway used by the cell depends on the type of DNA damage that has occurred. The types of DNA repair that we are focusing on relate directly to cancer. These involve a break in BOTH strands of DNA, which can be the result of ionizing radiation or other DNA damaging agents. This type of DNA damage is called Double Strand Breaks (DSB's). There are two main pathways used by cells to repair DSB's in DNA, one is Homologous Recombination (HR), the other is Non-Homologous End Joining (NHEJ). This page of our website focuses on the HR pathway (there is a separate web page for NHEJ repair if you select PKcs from the gene list when you sign on to this page).

Many proteins are involved in the complex HR pathway to repair DSB's in DNA. There is a graphic above that depicts the HR pathway (if you click on the graphic, it will enlarge and become a bit easier to follow). While complicated, the DSB at the top right of the graphic is acted upon by a series of proteins in the circle of steps shown that ultimately lead to the complete and accurate repair of the DSB in the DNA.

Some of the proteins involved in the HR DSB repair pathway are MRE11, NBS1, RAD50. These three proteins make up the MRN complex. This complex detects DSB's in the DNA. Once the DSB is found by the MRN complex, the MRN complex functions with BRCA1 and CtIP to resect the DSB’s to form single stranded DNA “tails”. Meanwhile, DSB's also activate the ATM protein, which in turn acts upon CHK2 to activate it, as well as directly activating the tumor suppressor TP53. TP53 can cause cell cycle delay, giving the cell time to repair DNA breaks or mistakes before the cell cycle leading to division resumes. In the next step, RPA binds to the single stranded DNA "tails" that have been created by BRCA1 and CtIP in conjunction with the MRN. The binding of RPA activates another protein called ATR. ATR has many important functions, including activating CHK1, which can cause cell cycle delay giving cells time to repair DNA. ATR also regulates BRCA1 which recruits a bound group of proteins including PALB2/BRCA2/RAD51. In the next step, RAD51 displaces the RPA that is on the single stranded DNA, with the involvement of BRCA2/PALB2 and RAD51c. BRCA1/BARD1 helps RAD51 coated single stranded DNA invade double stranded DNA with homologous sequences to form a DNA repair loop. With the help of DNA polymerases, the repair loop creates the opportunity to use the intact homologous DNA as a template to correctly repair DSB’s. Enzymes called ligases reconnect the ends of the DNA, leading to complete and accurate repair of the DSB in DNA.

After studying familial cancer syndromes, germline or inherited BRCA1 and BRCA2 were identified a while ago as proteins that when altered by mutation, cause certain cancers. Some BRCA1 and BRCA2 genes become mutated somatically, meaning in a non-inherited way. When either gene is mutated, the resulting protein cannot perform its role in DNA repair correctly. This turns out to be true for other proteins in the HR pathway as well. Recently, scientists have found mutations in many of the other genes that encode the proteins involved in the HR pathway. Mutations in HR pathway members include MRE11, NBS1, RAD50, ATM, CHK2, BRCA1, PALB2, RAD51, BRCA2, BARD1, and RAD51c (these are depicted in red in the above graphic). This remarkable number of mutations in proteins involved in the DNA repair pathway found in cancer highlights how important the HR DSB DNA repair pathway is in cells. The mutations in HR pathway proteins result in proteins that do not function properly in their role in DNA repair. Without proper function of the proteins involved in DNA repair, DNA mistakes or breaks are not properly repaired, and the damaged DNA contributes to the development of cancer.

ATR is only rarely mutated in cancer, however, the frequent mutations in ATM result in cells that are completely reliant on the ATR pathway to repair DSB's in the DNA. This has therapeutic implications for treatment of tumors that have mutations in the HR DNA repair pathway.

Testing for mutations in the many genes/proteins involved in DNA repair discussed above is available in the MGH genetics lab. Treatment as well as clinical trials studying new drugs that target defects in these proteins-including ATR- are available at the MGH Cancer Center.



PubMed ID's
27617969, 24003211, PMC2988877
Expand Collapse ATR  in Leukemias
Alterations in the gene encoding ATR are not found in leukemia. ATR is an important protein in the DNA repair pathway. ATR controls a signaling pathway in the cell by activating CHK1, which causes a delay in the cell cycle (see graphic above). Without this delay, cells would not have time to repair broken or damaged DNA. The accumulation of damaged DNA in the cell can lead to cancer.

ATR has become an important protein to inhibit with drugs in cancer. Cancer cells often have genetic alterations in other proteins in the DNA repair pathway (see red proteins in graphic above). If the ATM protein is mutated and unable to cause cell cycle arrest for DNA repair, then ATR is the only option for cancer cells to use to delay the cell cycle and repair DNA. Drugs targeting ATR block this pathway, leaving cancer cells no way to pause the cell cycle to achieve DNA repair. The tumor cells die as the result of accumulated damaged or broken DNA.

Alterations in the gene encoding ATR are not found in leukemia. ATR is an important protein in the DNA repair pathway. ATR controls a signaling pathway in the cell by activating CHK1, which causes a delay in the cell cycle (see graphic above). Without this delay, cells would not have time to repair broken or damaged DNA. The accumulation of damaged DNA in the cell can lead to cancer.

ATR has become an important protein to inhibit with drugs in cancer. Cancer cells often have genetic alterations in other proteins in the DNA repair pathway (see red proteins in graphic above). If the ATM protein is mutated and unable to cause cell cycle arrest for DNA repair, then ATR is the only option for cancer cells to use to delay the cell cycle and repair DNA. Drugs targeting ATR block this pathway, leaving cancer cells no way to pause the cell cycle to achieve DNA repair. The tumor cells die as the result of accumulated damaged or broken DNA.

Expand Collapse No mutation selected
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.
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Your Matched Clinical Trials

Trial Matches: (D) - Disease, (G) - Gene
Trial Status: Showing Results: 1-10 of 34 Per Page:
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Protocol # Title Location Status Match
NCT03106428 A Multiple Ascending Dose Study of MEDI7247 in Patients With Selected Relapsed/Refractory Hematological Malignancies A Multiple Ascending Dose Study of MEDI7247 in Patients With Selected Relapsed/Refractory Hematological Malignancies MGH Open D
NCT02290951 A Phase 1 Study to Investigate the Safety and Tolerability of REGN1979 in Patients With CD20+ B-Cell Malignancies A Phase 1 Study to Investigate the Safety and Tolerability of REGN1979 in Patients With CD20+ B-Cell Malignancies MGH Open D
NCT02049515 A Phase 3 Extension Study of Duvelisib and Ofatumumab in Patients With CLL/SLL Previously Enrolled in Study IPI-145-07 A Phase 3 Extension Study of Duvelisib and Ofatumumab in Patients With CLL/SLL Previously Enrolled in Study IPI-145-07 MGH Open D
NCT02677922 A Safety and Efficacy Study of Oral AG-120 Plus Subcutaneous Azacitidine and Oral AG-221 Plus Subcutaneous Azacitidine in Subjects With Newly Diagnosed Acute Myeloid Leukemia (AML) A Safety and Efficacy Study of Oral AG-120 Plus Subcutaneous Azacitidine and Oral AG-221 Plus Subcutaneous Azacitidine in Subjects With Newly Diagnosed Acute Myeloid Leukemia (AML) MGH Open D
NCT02848248 A Safety Study of SGN-CD123A in Patients With Acute Myeloid Leukemia A Safety Study of SGN-CD123A in Patients With Acute Myeloid Leukemia MGH Open D
NCT02537613 A Study of Ibrutinib + Obinutuzumab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia A Study of Ibrutinib + Obinutuzumab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia MGH Open D
NCT02993523 A Study of Venetoclax in Combination With Azacitidine Versus Azacitidine in Treatment Naïve Subjects With Acute Myeloid Leukemia Who Are Ineligible for Standard Induction Therapy A Study of Venetoclax in Combination With Azacitidine Versus Azacitidine in Treatment Naïve Subjects With Acute Myeloid Leukemia Who Are Ineligible for Standard Induction Therapy MGH Open D
NCT02997202 A Trial of the FMS-like Tyrosine Kinase 3 (FLT3) Inhibitor Gilteritinib Administered as Maintenance Therapy Following Allogeneic Transplant for Patients With FLT3/Internal Tandem Duplication (ITD) Acute Myeloid Leukemia (AML) A Trial of the FMS-like Tyrosine Kinase 3 (FLT3) Inhibitor Gilteritinib Administered as Maintenance Therapy Following Allogeneic Transplant for Patients With FLT3/Internal Tandem Duplication (ITD) Acute Myeloid Leukemia (AML) MGH Open D
NCT02345850 Calcineurin Inhibitor-Free Interventions for Prevention of Graft-versus-Host Disease (BMT CTN 1301) Calcineurin Inhibitor-Free Interventions for Prevention of Graft-versus-Host Disease (BMT CTN 1301) MGH Open D
NCT01406756 Combination Chemotherapy in Treating Young Patients With Newly Diagnosed High-Risk Acute Lymphoblastic Leukemia Combination Chemotherapy in Treating Young Patients With Newly Diagnosed High-Risk Acute Lymphoblastic Leukemia MGH Open D
Trial Status: Showing Results: 1-10 of 34 Per Page:
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