2.1. Acute promyelocytic leukemia

MedlinePlus Genetics provides information about Acute promyelocytic leukemia

2.2. Cytogenetically normal acute myeloid leukemia

Mutations in the NPM1 gene are involved in a form of blood cell cancer known as cytogenetically normal acute myeloid leukemia (CN-AML). While large chromosomal abnormalities can be involved in the development of acute myeloid leukemia, about half of cases do not have these abnormalities; these are classified as CN-AML. Approximately 64 percent of people with CN-AML have a mutation in the NPM1 gene.

The NPM1 gene mutations involved in CN-AML are called somatic mutations; they are found only in cells that become cancerous and are not inherited. These mutations occur in a region of the gene designated exon 12. They change the blueprint used to make the nucleophosmin protein, leading to production of a protein with an altered sequence of protein building blocks (amino acids). The alterations change the amino acid tryptophan at protein position 290 and often the tryptophan at position 288. These two tryptophans are important for localization of the protein in the nucleolus. The new sequence also provides a signal (called the nuclear export signal) for the protein to be moved out of the nucleus. As a result, the nucleophosmin protein is found in the cytoplasm rather than the nucleolus.

It is not clear how abnormal localization of the nucleophosmin protein leads to acute myeloid leukemia. Research suggests that it affects the function of the ARF protein. Because of its interaction with the altered nucleophosmin, the ARF protein is also found in the cytoplasm in cells with these genetic changes. In addition, the altered nucleophosmin protein is unable to protect ARF from being broken down. A reduction of the tumor suppressor function of the ARF protein is believed to lead to the uncontrolled production of abnormal white blood cells that occurs in acute myeloid leukemia. Other effects of NPM1 gene mutations may also be involved in the development of leukemia.

2.3. Other cancers

A genetic rearrangement (translocation) involving the NPM1 gene is found in another blood cell cancer known as anaplastic large cell lymphoma (ALCL). In ALCL, white blood cells known as T cells grow and divide uncontrollably and often form tumors in the lymph nodes. The translocation involved in this cancer, known as t(2;5), fuses part of the NPM1 gene on chromosome 5 with part of another gene called ALK on chromosome 2. This rearrangement is a somatic mutation.

The protein produced from the fusion gene is called NPM-ALK. Like the normal activated ALK protein, NPM-ALK turns on signaling pathways that stimulate cell growth and division (proliferation) and maturation (differentiation). Unlike ALK, the NPM-ALK protein is active all the time, which causes uncontrolled cell proliferation and leads to ALCL.