Leukemias, HRAS, Q61H (c.183G>T)

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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 HRAS  - General Description
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HRAS is a gene that provides the code for making an enzyme called HRAS that converts a molecule called GTP into GDP. This enzyme is part of a signaling pathway (MAP kinase signaling cascade) that relays chemical signals from the outside of the cell to the cell's nucleus, telling the cell when to grow and divide. When it is in its off position, HRAS is attached (bound) to GDP and cannot send signals to the nucleus. But when a GTP molecule arrives and binds to HRAS, HRAS is activated and sends its signal. It then immediately changes the GTP into GDP and returns to the off position.

When mutated, HRAS can act as an oncogene, causing normal cells to become cancerous. The mutations can shift HRAS into the on position all the time, resulting in signaling that tells the cell to grow and divide abnormally. Some mutations that can lead to cancer are inherited, but that's not the case with these HRAS mutations. They're known as somatic mutations because, instead of coming from a parent and being present in every cell (hereditary), they are acquired during the course of a person's life and are found only in cells that become cancerous. Somatic HRAS mutations have been associated with some cases of bladder, thyroid and kidney cancers.

Source: Genetics Home Reference
HRAS (v-Ha-ras Harvey rat sarcoma viral oncogene homolog) is a member of the closely related RAS gene family that also includes KRAS and NRAS. These RAS members are small GTPases that mediate extracellular signals to the downstream effectors RAF, PI3K and RALGDS. RAS members are involved in regulating diverse cellular processes including survival, proliferation and differentiation. While activating mutations in the Ras genes lead to sustained GTPase activation that contributes to oncogenesis, each oncogene exerts clear differences. Mutational hotspots in HRAS reside primarily in amino acid residues 12, 13 or 61.

Source: Genetics Home Reference
PubMed ID's
21779495
Expand Collapse Q61H (c.183G>T)  in HRAS
The HRAS Q61H mutation arises from a single nucleotide change (c.183G>T) and results in an amino acid substitution of glutamine (Q) at position 61 by a histidine (H).
The HRAS Q61H mutation arises from a single nucleotide change (c.183G>T) and results in an amino acid substitution of glutamine (Q) at position 61 by a histidine (H).

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Your Matched Clinical Trials

Trial Matches: (D) - Disease, (G) - Gene, (M) - Mutation
Trial Status: Showing Results: 1-10 of 15 Per Page:
12Next »
Protocol # Title Location Status Match
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
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
NCT02421939 A Study of ASP2215 Versus Salvage Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With FMS-like Tyrosine Kinase (FLT3) Mutation A Study of ASP2215 Versus Salvage Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With FMS-like Tyrosine Kinase (FLT3) Mutation 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
NCT02577406 An Efficacy and Safety Study of AG-221 (CC-90007) Versus Conventional Care Regimens in Older Subjects With Late Stage Acute Myeloid Leukemia Harboring an Isocitrate Dehydrogenase 2 Mutation An Efficacy and Safety Study of AG-221 (CC-90007) Versus Conventional Care Regimens in Older Subjects With Late Stage Acute Myeloid Leukemia Harboring an Isocitrate Dehydrogenase 2 Mutation MGH Open D
NCT01830777 Brentuximab Vedotin + Chemo for AML Brentuximab Vedotin + Chemo for AML MGH Open D
NCT02642965 Liposomal Cytarabine-Daunorubicin CPX-351, Fludarabine Phosphate, Cytarabine, and Filgrastim in Treating Younger Patients With Relapsed or Refractory Acute Myeloid Leukemia Liposomal Cytarabine-Daunorubicin CPX-351, Fludarabine Phosphate, Cytarabine, and Filgrastim in Treating Younger Patients With Relapsed or Refractory Acute Myeloid Leukemia MGH Open D
NCT02841540 Phase 1 Trial to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of Splicing Modulator H3B-8800 for Subjects With Myelodysplastic Syndromes, Acute Myeloid Leukemia, and Chronic Myelomonocytic Leukemia Phase 1 Trial to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of Splicing Modulator H3B-8800 for Subjects With Myelodysplastic Syndromes, Acute Myeloid Leukemia, and Chronic Myelomonocytic Leukemia MGH Open D
NCT02228772 Phase I Study of MLN 9708 in Addition to Chemotherapy for the Treatment of Acute Lymphoblastic Leukemia in Older Adults Phase I Study of MLN 9708 in Addition to Chemotherapy for the Treatment of Acute Lymphoblastic Leukemia in Older Adults MGH Open D
NCT02312102 Phase I Study of Velcade and Lenalidomide in Patients With Relapsed AML and MDS After Allogeneic Stem Cell Transplantation Phase I Study of Velcade and Lenalidomide in Patients With Relapsed AML and MDS After Allogeneic Stem Cell Transplantation MGH Open D
Trial Status: Showing Results: 1-10 of 15 Per Page:
12Next »
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