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Acute myeloid leukemia : Identification of the genetic alteration responsible for uncontrolled cellular proliferation

20.12.2005

Blood taken from a normal mouse The blue coloring is characteristic of blood cells called blasts, which are proliferating. Blasts are in a small minority. © F. Moreau-Gachelin/Institut Curie

Blood taken from a leukemic mouse In blood taken from a leukemic mouse, the proliferating cells are much more numerous, indicating the presence of leukemic cells. © F. Moreau-Gachelin/Institut Curie

At the Institut Curie, an Inserm team has just identified the molecular mechanism long suspected to account for the formation of malignant cells in the most frequent leukemia – acute myeloid leukemia. For a cell to become leukemic, it must not only proliferate but also no longer become specialized. Mutations in its gene confer autonomous activity on the Kit receptor, thereby allowing cells to proliferate in the absence any external signal.This study was published in the 12 December 2005 issue of Cancer Cell.

Blood cells are produced in the bone marrow from stem cells. In response to growth factors, stem cells differentiate into precursor cells of three blood lines: red blood cells (also called erythrocytes), white blood cells (lymphocytes, macrophages…) and platelets. The cells are only released into the blood when they reach maturity.

Leukemias are malignant blood diseases characterized by the uncontrolled proliferation of blood cells. Lymphoid leukemias, which affect lymphocytes, are distinct from myeloid leukemias, which affect the precursors of all the other blood cell lines. The acute nature of leukemia is reflected in a complete absence of mature cells and in the presence in the bone marrow of numerous cells blocked at an early stage of their maturation.

In France, about 5 000 people are diagnosed with acute leukemia each year. The prognosis varies greatly from one type of leukemia to another. Acute myeloid leukemia accounts for 70% of acute leukemias, without regard to age. Its frequency peaks around 60 years of age. Erythroleukemia(1) is a type of myeloid leukemia.

A two-step mechanism

The molecular mechanisms underlying leukemia are legion and rare exceptions apart there is no single cause. These mechanisms are multi-stage. Murine cancer models used in research, like human tumors, are the result of accumulated genetic anomalies that enable cells to escape the control mechanisms involved in cell differentiation, growth and death by apoptosis.

In the case of erythroleukemia, researchers suspect the existence of a so-called “two-hit” model, although no verification has yet been forthcoming. Erythroleukemia is the consequence of a collaboration between two types of mutations, one that confers a proliferative advantage and one that blocks differentiation.

Uncontrolled proliferation results from mutation of a receptor

Françoise Moreau-Gachelin(2) and her Inserm team at the Institut Curie have now found evidence for this two-step mechanism and have shed light on how it works. They have worked on mice carrying a mutant gene that encodes the transcription factor(3) spi-1/PU.1, whose overexpression is involved in the onset of murine erythroleukemia, which therefore constitutes a good model for the study of human erythroleukemia.

Murine leukemia is characterized by a first event, which blocks the differentiation of precursor cells of the erythrocyte line, and a second event, which induces uncontrolled proliferation of the cells. The mechanism underlying the first event is known to be overexpression of the transcription factor spi-1/PU.1. The mechanism responsible for the second event was until now unknown.

By investigating the sequence of the gene coding for the Kit receptor, Françoise Moreau-Gachelin’s team discovered that this gene was mutated in 86% of the tumors studied.

Acting as a sort of switch, the Kit receptor relays information to the inside of the cell by activating its signaling pathways following receipt of a message from the outside. Françoise Moreau-Gachelin and her colleagues had shown before that some signaling pathways acting downstream of the receptors are “on” in leukemic cells and activate the proliferation of cells in the absence of an order from outside. They have now shown that the mutant Kit receptor is responsible for this uncontrolled activation.

The two-hit model has been validated: for a healthy cell to become malignant, the spi-1/PU.1 gene must be abnormally expressed and the Kit gene must be mutated. Mutation of the Kit gene is therefore a major event responsible for the transformation erythrocyte precursors into malignant cells during acute myeloid leukemia. It is vital to identify all the players in oncogenesis if we are to design new and more effective treatments for the fight against acute myeloid leukemia.

Notes

(1) Erythroleukemia affects red blood cells, also called erythrocytes.

(2) “Leukemogenesis and transcription factor Spi” team in Inserm U 528 “Signal transduction and oncogenesis” headed by Dr Olivier Delattre.

(3) A transcription factor is a protein which controls the expression of a gene.