Activation of Ras in hematologic malignancies
| Malignancy . | Type of activation . | Frequency (%) . | Reference nos. . |
|---|---|---|---|
| Point mutations of RAS | |||
| Multiple myeloma | N-, K-RAS | 30-40 | 74,76-78 |
| Plasma cell leukemia | N-, K-RAS | 60-70 | 74, 76-78 |
| Acute myeloid leukemia (AML) | N-, K-RAS | 20-30 | 60-71 |
| Childhood AML | N-, K-RAS | 20-40 | 64, 72 |
| Acute lymphoblastic leukemia | N-, K-RAS | 20 | 68, 69, 75 |
| Chronic myelomonocytic leukemia (CMML) | N-, K-RAS | 50-70 | 65, 73, 80 |
| Juvenile myelomonocytic myeloid leukemia (JMML) | N-RAS | 30 | 107 |
| Mutation of c-Kit/c-FMS receptor family | |||
| Myeloproliferative disorder, mastocytosis | c-kit | 10 | 83-85 |
| AML | FLT-3 | 20 | 87 |
| CSF-1(c-FMS) | 10-20 | 81, 82 | |
| Fusion tyrosine kinases | |||
| Chronic myeloid leukemia | Bcr-Abl, t(9;22), Ras-GTP | 95 | 95-97 |
| CMML | Tel-PDGFRβ, t(5;12) | 91, 92 | |
| AML | Tel-Abl, t(12;9) | 93, 94 | |
| Anaplastic large cell lymphoma | Npm-Alk, t(2;5) | 30-40 | 89, 90 |
| Inactivation of tumor suppressors | |||
| JMML | Inactivation of NF-1, (Ras-GAP) | 99-108 |
| Malignancy . | Type of activation . | Frequency (%) . | Reference nos. . |
|---|---|---|---|
| Point mutations of RAS | |||
| Multiple myeloma | N-, K-RAS | 30-40 | 74,76-78 |
| Plasma cell leukemia | N-, K-RAS | 60-70 | 74, 76-78 |
| Acute myeloid leukemia (AML) | N-, K-RAS | 20-30 | 60-71 |
| Childhood AML | N-, K-RAS | 20-40 | 64, 72 |
| Acute lymphoblastic leukemia | N-, K-RAS | 20 | 68, 69, 75 |
| Chronic myelomonocytic leukemia (CMML) | N-, K-RAS | 50-70 | 65, 73, 80 |
| Juvenile myelomonocytic myeloid leukemia (JMML) | N-RAS | 30 | 107 |
| Mutation of c-Kit/c-FMS receptor family | |||
| Myeloproliferative disorder, mastocytosis | c-kit | 10 | 83-85 |
| AML | FLT-3 | 20 | 87 |
| CSF-1(c-FMS) | 10-20 | 81, 82 | |
| Fusion tyrosine kinases | |||
| Chronic myeloid leukemia | Bcr-Abl, t(9;22), Ras-GTP | 95 | 95-97 |
| CMML | Tel-PDGFRβ, t(5;12) | 91, 92 | |
| AML | Tel-Abl, t(12;9) | 93, 94 | |
| Anaplastic large cell lymphoma | Npm-Alk, t(2;5) | 30-40 | 89, 90 |
| Inactivation of tumor suppressors | |||
| JMML | Inactivation of NF-1, (Ras-GAP) | 99-108 |
Ras proteins are small GTPases that cycle between 2 conformations induced by the binding of GDP or GTP. In the active, GTP-bound conformation, Ras binds to and activates effector proteins such as Raf kinases, PI-3K, and Ral-GDS. Mutations in codons 12, 13, or 61 of theRAS genes lead to activated Ras proteins that have lost the ability to become inactivated and thus stimulate growth autonomously. Activated tyrosine receptor kinases, which are upstream of Ras (eg, mutated c-Kit, c-FMS, FLT-3, or activated fusion tyrosine kinases such as BCR-Abl, Tel-Abl, Npm-Alk, and Tel-PDGFRβ), may also cause elevated levels of active, GTP-bound Ras and thus stimulate cell proliferation. The loss of the tumor suppressor NF-1, a Ras-GTPase activating protein (Ras-GAP), also causes Ras activation.