Other Mutations Implicated in the Pathogenesis of AML

Apart from the fusion genes resulting from chromosomal translocations identified in AML, it has become apparent over the last few years that other mutations play a role in the pathogenesis of the disease.2,3 These fall into three categories: (1) mutations disrupting the function of transcription factors that are implicated in hematopoiesis, (2) mutations involving receptor tyrosine kinases and other components of the signaling cascades, and (3) mutations in the nucleophosmin (NPM1) gene encoding nucleophosmin.

Mutations in Genes Encoding Transcription Factors

The function of a number of key transcription factors that regulate normal hematopoietic development is disrupted in AML due to the presence of inactivating or dominant negative mutations (see Table 30-3). The first such example to be identified involved the AML1 gene, which was found to be mutated in familial platelet disorder (FPD; reviewed in Reference 2). This rare autosomal dominant condition is characterized by progressive pancytopenia and dysplasia and ultimately progresses to AML in a high percentage of cases. AML1 is mutated in approximately 3% to 5% of sporadic cases of AML, particularly those with acquired trisomy 21 and cases with minimal differentiation (French-American-British [FAB] type M0; details of FAB classification of AML are provided in Reference 7). Indeed, AML1 mutations are detected in up to 25% of M0 cases and are frequently biallelic.

The CCAAT/enhancer binding protein-a (CEBPA), which plays an important role in granulopoiesis, also is a relatively common target in AML, being potentially deregulated by the AML1-ETO and PML-RARa oncoproteins. Furthermore, mutations involving CEBPA are present in approximately 10% of cases of AML.3,8

GATA1 is a key transcription factor involved in megakaryocytic differentiation and is mutated in cases of transient abnormal myelopoiesis (TAM) and acute megakaryoblastic leukemia (AMKL, FAB type M7) arising in infants with Down syndrome.9 The role of PU.1, which has been implicated in normal differentiation of multiple hematopoietic lineages, in the pathogenesis of AML is somewhat controversial and awaits further investigation. A number of studies have detected partial tandem duplications of the MLL gene in AML, particularly in cases with trisomy 11 (reviewed in Reference 1).

Mutations in Genes Encoding Components of Signal Transduction Pathways

Activating mutations in hematopoietic tyrosine kinases are frequent events in AML.2 Such mutations are likely to confer a proliferative advantage, although evidence to date suggests that they are unlikely to be the primary transforming event. Mutation of the FLT3 gene encoding Fms-like tyrosine kinase 3 is one of the most common genetic lesions identified in AML thus far, being detected in almost one third of cases (reviewed in Reference 5). The majority are length mutations (internal tandem duplications, ITDs) involving the juxtamembrane region of the receptor, whereas approximately 4% to 7% of AML cases have mutations involving the activation loop. Nevertheless, both

Table 30-2. Frequencies of Specific Cytogenetic Abnormalities Determined in a Series of 1584 Patients Derived from the MRC AML10 Trial

Chromosomal Aberrations

Frequency in

Associated with AML

Children and

(grouped according to underlying Molecular

Younger Adults

Associated Clinical

molecular abnormality) Consequence

(0-55 years)


Core binding factor gene rearrangement:


AML1 (CBFA2) gene at 21q22 or

CBFB gene at 16q22

t(3;21)(q26;q22) EAP/MDS1/EVI1-AML1 fusion Rare

t(8;21)(q22;q22) AML1-ETO fusion


Often AML M2, associated with chloromas

inv(16)(p13q22)/t(16;16)(p13;q22) CBFB-MYH11 fusion


M4 with abnormal eosinophils (M4Eo)

t(16;21)(q24;q22) MTG16-AML1 fusion


Therapy-related AML

RARA gene rearrangement (17q12~21):


5 fusion partners of RARA identified to date;*

associated with APL

t(5;17)(q35;q12~21) NPM-RARA fusion


AML M3, ATRA sensitive

t(11;17)(q23;q21) PLZF-RARA fusion


AML M2/M3, ATRA and arsenic resistant

t(15;17)(q22;q12~21) PML-RARA fusion


AML M3, ATRA and arsenic sensitive

MLL gene rearrangement (11q23):


More than 30 fusion partners identified to

t(6;11)(q27;q23) AF6-MLL fusion


date; therefore, only the commonest

t(9;11)(p21~22;q23) AF9-MLL fusion


abnormalities detected in AML are listed;

t(10;11)(p11~13;q23) AF10-MLL fusion


associated with M4 and more commonly

t(11;19)(q23;p13.3) MLL-ENL fusionf


M5. Some cases are therapy related,



secondary to topoisomerase Il-targeted

drugs, particularly etoposide

Involvement of zinc finger encoding genes by rearrangements of 3q:

EVI1 gene at 3q26 or MDS/EVI1 homologue MEL1 at 1p36

inv(3)(q21q26)/t(3;3)(q21;q26) EVI1 overexpression


Trilineage dysplasia, dysmegakaryopoiesis

t(3;12)(q26;p13) MDS1/EVI1-TEL fusion


t(1;3)(p36;q21) MEL1 overexpression


Involvement of genes encoding factors involved in signal transduction: ABL at 9q34

t(9;22)(q34;q11) BCR-ABL fusion


Typically associated with CML and ALL

Detected in AML M0/1 and 2

Nuclear pore component genes:

CAN (NUP214) at 9q34

NUP98 at 11p15

t(6;9)(p23;q34) DEK-CAN fusion


AML M2 with basophilia

t(11)(p15) NUP98 fusions


NUP98 rearrangements commonly associated

with previous exposure to topoisomerase

II-targeted drugs

Other genes encoding transcriptional regulators/chromatin modulators, including:

MOZ gene rearrangements at 8p11

CBP gene rearrangements at 16p13

t(1;22)(p13;q13) OTT-MAL fusion


Associated with infant AML M7

inv(8)(p11q13) MOZ-TIF2 fusion


AML M4/5 with prominent erythrophagocytosis

t(8;16)(p11;p13) MOZ-CBP fusion


t(8;22)(p11;q13) MOZ-P300 fusion


t(10;16)(q22;p13) MORF-CBP fusion


Childhood M5a

Ets family transcriptional factor genes:

TEL (ETV6) gene rearrangements at 12p13

ERG gene rearrangement at 21q22

t(12)(p13) TEL (ETV6) fusions


Associated with wide range of FAB types

t(16;21)(p11;q22) FUS-ERG fusion


Reported in AML M1,2,4,5,7

Other recurrent translocations in AML:

NPM on 5q34~35

t(3;5)(q25;q34) NPM-MLF1 fusion


NPM is also disrupted in t(5;17) in APL and

t(2;5) in anaplastic lymphoma

AF10 on 10p12~p13

t(10;11)(p12~p13;q14~q21) CALM-AF10 fusion


Associated with poorly differentiated AML;

also detected in T-ALL

*NuMA-RARA and STAT5b-RARA associated with t(11;17)(q13;q21) and der(17), respectively, have been identified in only single patients.

fThree different MLL fusion partners have been identified in cases

with t(11;19), with ENL being the commonest in AML.

ATRA, all-trans retinoic acid.

Table 30-3 Genes Subject to Mutation in AML


Frequency of Mutation in AML

Associated Clinical Features

Transcription Factors


3% (excluding M0)

High frequency in AML M0 (~21%) and AML with acquired trisomy 21



Associated with AML M1, M2, and standard-risk karyotype;mutations not detected in AMLl-ETO-positive AML



Mutations detected in transient abnormal myelopoiesis and AML M7 in Down syndrome


Not established

Reported in cases of M0, M4, and M5*

MLL Cleavage ITD

3% 3%

DNA cleavage at TOPOII site More common in cases with trisomy 11

Tyrosine Kinases and Other Signal Transduction Molecules


Activation loop mutationst

20-25% 4-7%

More common in AML with PML-RARa (particularly M3v), DEK-CAN/t(6;9), and cases with normal karyotype;associated with higher presenting blast counts;ITD relatively rare in cases with adverse karyotypic features



More common in core binding factor leukemias;potential cooperating event in leukemogenesis;more common in AML with trisomy 4



Does not appear to be an independent prognostic indicator



PTPN11 encodes SHP-2;mutations associated with AML M5 and monosomy 7

Chromatin Modulators



Mutated in >50% of normal karyotype AML;associated with FLT3-ITD, M5 morphology, CD34 negativity, and elevated leukocyte count

*Based on report by Mueller et al.,4 but findings remain to be confirmed by other studies. tPoint mutations (e.g., D835/I836) and length mutations (FLT3-840GS).56

types of mutation lead to constitutive activation of the receptor. FLT3 ITDs are associated with higher presenting peripheral blast counts and are commonly detected in AML with normal karyotype and in PML-RARA-associated APL, particularly the hypogranular variant form (M3v).

Mutations in NRAS or KRAS also are relatively common in AML, occurring in approximately 20% of cases. Interestingly, these rarely coexist with mutations of FLT3. Indeed, RAS mutations are quite common in CBF leukemias, while FLT3 ITDs are rare, the converse of what occurs in APL. The RAS pathway also is activated in the presence of mutations of the PTPN11 gene, which encodes the SHP2 tyrosine phosphatase. PTPN11 is commonly mutated in juvenile myelomonocytic leukemia (JMML) but also is involved in approximately 4% of AML, being associated with M5 morphology, elevated leukocyte count, and monosomy 7.10,11 Mutations affecting KIT occur at a similar overall frequency in AML but are particularly common in CBF leukemias, raising the possibility that in this context they could provide a second hit, contributing to leukemogenesis.

Nucleophosmin Mutations

Recently, mutation of NPM1, which is a multifactorial nucleocytoplasmic shuttling protein implicated in regulating gene expression and the ARF-TP53 tumor-suppressor pathway, has been identified as a common mechanism in the pathogenesis of AML.12 Mutations disrupt C-terminal tryptophan residues that are required for nuclear localization, leading to a characteristic cyto-plasmic staining pattern by immunohistochemistry using antibodies against the NPM1 protein (that are in common use in diagnosis of lymphoma with NPM-ALK fusion).12 Overall, approximately 35% of AML have NPM1 mutations; however, mutation is particularly prevalent among cases with a normal karyotype (48-62%).1214 NPM1 mutations are associated with FLT3 ITD, CD34 negativity, presentation with elevated leukocyte count, and M4/M5 FAB type.12-14

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