Based on Gene Study, AML Leukemia Has 11 Subtypes

Genetic mutations shed light on 11 different AML subtypes.. Photo©bodym

Leukemia is not one disease, but many. Scientists are beginning to understand how even a single, specific type of leukemia has subtypes that differ in important ways.

Four main types of leukemia are based on whether they are acute or chronic, and myeloid or lymphocytic leukemias, and these main categories are as follow:

About AML

Acute myelogenous leukemia is a cancer of the bone marrow—the spongy insides of bones, where blood cells are made—and it is also a cancer of the blood.

AML is considered an “acute” leukemia because it progresses rapidly. The myelogenous part of the name comes from the myeloid cells—a group of cells that normally develop into the various types of mature blood cells, such as red blood cells, white blood cells and platelets.

AML has many aliases: Acute myelogenous leukemia is also known as acute myeloid leukemia, acute myeloblastic leukemia, acute granulocytic leukemia and acute nonlymphocytic leukemia.

AML can affect people of all ages. The World Health Organization's 2012 GLOBOCAN project suggested some 352,000 people worldwide had AML, and the disease is becoming more prevalent as populations age.

Signs and symptoms of AML include:

  •     Fever
  •     Bone pain
  •     Lethargy and fatigue
  •     Shortness of breath
  •     Pale skin
  •     Frequent infections
  •     Easy bruising
  •     Unusual bleeding, such as frequent nosebleeds and bleeding from the gums


The classification of AML based on microscopic appearance of the cancer cells, or morphology, is being augmented by new discoveries about the genetic changes or mutations that are involved in different forms of this malignancy.

Researchers at the Wellcome Trust Sanger Institute and collaborators recently added to the knowledge base, reporting on genetic mutations that help shape the understanding of AML—further shifting the concept of AML from that of a single disorder to one with at least 11 different genetic varieties of malignancy, with differences that can help explain variable survival times among young patients with AML.

The researchers published their study on the genetics of AML in the June 2016 issue of “New England Journal of Medicine,” and experts believe these findings could improve clinical trials and impact the way patients with AML are diagnosed and treated in the future.

The NEJM Study

Researchers studied 1,540 patients with AML who were enrolled in clinical trials. They analyzed more than 100 genes known to cause leukemia with the goal of identifying “genetic themes” behind the development of the disease.

They found that the patients with AML could be divided into at least 11 major groups, each with differing clusters of genetic changes and differing characteristics and features.

According to the study, most patients had a unique combination of genetic changes driving their leukemia, which may help to explain why AML shows such variability in survival rates.


Knowing the genetic make-up of a patient’s leukemia can improve the ability to predict whether current treatments would be effective. Information of this type might be used to design new clinical trials to develop the best treatments for each AML subtype; and eventually, more extensive genetic testing of AML at diagnosis could become more routine.

In the 2008 World Health Organization (WHO) classification system, scientists already started classifying adult AML into different “molecular groups,” including specific genetic changes or injuries to the chromosomes denoted as follows: t(15;17), t(8;21), inv(16)–t(16;16), t(6;9), inv(3)–t(3;3), MLL fusion genes, and provisionally, CEBPA or NPM1 mutations.

However, as illustrated in the recent NEJM study, the WHO molecular classifications do not work well for a large number of AML cases. In the study, 736 patients with AML, or 48 percent of them, would not have been classified based on the WHO molecular groups, even though 96 percent of the patients did, indeed, have so-called driver mutations—genetic changes that underlie the malignancy.

The discovery of many new leukemia genes, multiple driver mutations per patient, and complex mutation patterns prompted the investigators to reevaluate genomic classification of AML from the beginning.

Proposed AML Evaluation and Classification, Based on Genetic Mutations

Thus, the researchers went back to the drawing board to try to develop a new system to classify AML that makes use of the emerging information.

The most widely accepted classification and prognostic schemes for AML use the WHO classification – including the so-called cytogenetic lesions—for instance t(15;17)—together with NPM1, FLT3ITD, and CEBP, as listed above.

In light of the new study, authors recommended that, in the short term, TP53, SRSF2, ASXL1, DNMT3A, and IDH2 should be considered for incorporation into prognostic guidelines because they are common and exert a strong influence on clinical outcomes.

For AML classification, evaluation of "splicing-factor genes" RUNX1, ASXL1, and MLLPTD at diagnosis would identify patients in the “chromatin–spliceosome group.” This was the second largest group of AML patients in the study, and in contrast to the WHO classes of AML, no single genetic lesion defines this group.

Using this proposed system, 1,236 of the 1,540 patients with driver mutations could be classified into a single subgroup, and 56 patients met criteria for two or more categories. A total of 166 patients with driver mutations remained unclassified.

Background of Existing Classification Systems

AML is not staged like most other cancers. The outlook for a person with AML depends instead on other information, such as the subtype as determined by lab tests, as well as the patient’s age, and other lab test results.

AML subtypes can relate to an individual patient’s outlook and the best treatment. For example, the acute promyelocytic leukemia (APL) subtype is often treated using drugs that are different from those used for other subtypes of AML.

Two of the main systems that have been used to classify AML into subtypes are the French-American-British (FAB) classification and the newer World Health Organization (WHO) classification.

The French-American-British (FAB) classification of AML

In the 1970s, a group of French, American, and British leukemia experts divided AML into subtypes, M0 through M7, based on the type of cell from which the leukemia develops and how mature the cells are. This was based largely on how the leukemia cells looked under the microscope after routine staining.

FAB subtype                          Name

M0                                          Undifferentiated acute myeloblastic leukemia

M1                                          Acute myeloblastic leukemia with minimal maturation

M2                                          Acute myeloblastic leukemia with maturation

M3                                          Acute promyelocytic leukemia (APL)

M4                                          Acute myelomonocytic leukemia

M4 eos                                   Acute myelomonocytic leukemia with eosinophilia

M5                                          Acute monocytic leukemia

M6                                          Acute erythroid leukemia

M7                                          Acute megakaryoblastic leukemia

Subtypes M0 through M5 all start in immature forms of white blood cells. M6 AML starts in very immature forms of red blood cells, while M7 AML starts in immature forms of cells that make platelets.        

World Health Organization (WHO) classification of AML

The FAB classification system is useful and is still commonly used to group AML into subtypes, however knowledge advanced with respect to prognosis and outlook for various types of AML, and some of these advances were reflected in the 2008 World Health Organization (WHO) system.

The WHO system divides AML into several groups:

AML with certain genetic abnormalities

  • AML with a translocation between chromosomes 8 and 21
  • AML with a translocation or inversion in chromosome 16
  • AML with a translocation between chromosomes 9 and 11
  • APL (M3) with a translocation between chromosomes 15 and 17
  • AML with a translocation between chromosomes 6 and 9
  • AML with a translocation or inversion in chromosome 3
  • AML (megakaryoblastic) with a translocation between chromosomes 1 and 22

AML with myelodysplasia-related changes

AML related to previous chemotherapy or radiation

AML not otherwise specified (AML that doesn’t fall into one of the above groups and is therefore classified more like what was done in the FAB system):

  • AML with minimal differentiation (M0)
  • AML without maturation (M1)
  • AML with maturation (M2)
  • Acute myelomonocytic leukemia (M4)
  • Acute monocytic leukemia (M5)
  • Acute erythroid leukemia (M6)
  • Acute megakaryoblastic leukemia (M7)
  • Acute basophilic leukemia
  • Acute panmyelosis with fibrosis

Myeloid sarcoma (also known as granulocytic sarcoma or chloroma)

Myeloid proliferations related to Down syndrome

Undifferentiated and biphenotypic acute leukemias:
These are leukemias that have both lymphocytic and myeloid features. Sometimes called ALL with myeloid markers, AML with lymphoid markers, or mixed acute leukemias.

Above WHO categories were adapted from the American Cancer Society.


Papaemmanuil E, Gerstung M, et al. Genomic classification and prognosis in acute myeloid leukemia.  N Engl J Med. 2016;374(23):2209-21.

Wellcome Trust Sanger Institute. Acute myeloid leukemia is at least 11 different diseases.  Accessed June 2016.

American Cancer Society. How is acute myeloid leukemia classified? Accessed June 2016.

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