FAB Classification for Childhood Acute Myeloid Leukemia
WHO Classification System
Histochemical Evaluation
Immunophenotypic Evaluation
Cytogenetic Evaluation and Molecular Abnormalities
Classification of Myelodysplastic Syndromes in Children
Diagnostic Classification of Juvenile Myelomonocytic Leukemia

FAB Classification for Childhood Acute Myeloid Leukemia

The first most comprehensive morphologic-histochemical classification system for acute myeloid leukemia (AML) was developed by the French-American-British (FAB) Cooperative Group.[1-5] This classification system categorizes AML into the following major subtypes primarily based on morphology and immunohistochemical detection of lineage markers:

• M0: acute myeloblastic leukemia without differentiation.[6,7]  [Note: M0 AML, also referred to as minimally differentiated AML, does not express myeloperoxidase (MPO) at the light microscopy level, but may show characteristic granules by electron microscopy. M0 AML can be defined by expression of cluster determinant (CD) markers such as CD13, CD33 and CD117 (c-KIT) in the absence of lymphoid differentiation. To be categorized as M0, the leukemic blasts must not display specific morphologic or histochemical features of either AML or acute lymphoblastic leukemia (ALL).] M0 AML appears to be associated with an inferior prognosis in non-Down syndrome patients.[8]



• M1: acute myeloblastic leukemia with minimal differentiation but with the expression of MPO that is detected by immunohistochemistry or flow cytometry.



• M2: acute myeloblastic leukemia with differentiation.



• M3: acute promyelocytic leukemia (APL) hypergranular type. [Note: Identifying this subtype is critical since the risk of fatal hemorrhagic complication prior to or during induction is high and the appropriate therapy is different than for other subtypes of AML.] (Refer to the Acute Promyelocytic Leukemia section of this summary for more information on treatment options under clinical evaluation.)



• M3v: APL, microgranular variant. Cytoplasm of promyelocytes demonstrates a fine granularity, and nuclei are often folded. Same clinical, cytogenetic, and therapeutic implications as FAB M3.



• M4: acute myelomonocytic leukemia (AMML).



• M4Eo: AMML with eosinophilia (abnormal eosinophils with dysplastic basophilic granules).



• M5: acute monocytic leukemia (AMoL).
  • M5a: AMoL without differentiation (monoblastic).
  
  
  
  • M5b: AMoL with differentiation.
  
  
  



• M6: acute erythroid leukemia (AEL).



• M7: acute megakaryocytic leukemia (AMKL).  [Note: Diagnosis of M7 can be difficult without the use of flow cytometry as the blasts can be morphologically confused with lymphoblasts. Characteristically, the blasts display cytoplasmic blebs. Marrow aspiration can be difficult due to myelofibrosis, and marrow biopsy with reticulin stain can be helpful.]

Other extremely rare subtypes of AML include acute eosinophilic leukemia and acute basophilic leukemia.

Fifty percent to 60% of children with AML can be classified as having M1, M2, M3, M6, or M7 subtypes; approximately 40% have M4 or M5 subtypes. About 80% of children younger than 2 years with AML have an M4 or M5 subtype. The response to cytotoxic chemotherapy among children with the different subtypes of AML is relatively similar. One exception is FAB subtype M3, for which all-trans retinoic acid plus chemotherapy achieves remission and cure in approximately 70% to 80% of children with AML.

The World Health Organization (WHO) Classification System incorporates clinical, morphologic (i.e., FAB Classification information), immunophenotypic, cytogenetic, and molecular data.[9-11]

WHO classification of acute myeloid leukemias

1. AML with recurrent genetic abnormalities:
   1. AML with t(8;21)(q22;q22); (AML1 [CBFA]/ETO).
   2. AML with abnormal marrow eosinophils.
      1. inv(16)(p13q22).
      2. t(16;16)(p13;q22) (CBFB/MYH11).
   3. Acute promyelocytic leukemia (AML with t[15;17][q22;q12]) (PML/RARA) and variants (included as M3 in the FAB classification).
   4. AML with 11q23 (MLL) abnormalities.



2. AML with multilineage dysplasia (de novo or following a myelodysplastic syndrome-most cases of refractory anemia with excess of blasts in transformation fall in the latter category).



3. AML, therapy-related:
   1. Alkylating agent-related AML.
   2. Topoisomerase II inhibitor-related AML.



4. Acute leukemia of ambiguous lineage:
   1. Undifferentiated acute leukemia (leukemic blasts show no or minimal signs of morphologic and/or protein expression signs of maturation).
   
   
   
   2. Bilineal acute leukemia (more than one cell lineage that demonstrates leukemic transformation).
   
   
   
   3. Biphenotypic acute leukemia (a single population of leukemic blasts have simultaneous expression of protein expression markers of different hematopoetic cell lineages).
   
   
   



5. AML not otherwise categorized (including the FAB morphology-based M0 to M2, and M4 to M7 categories):
   1. AML minimally differentiated (FAB M0).
   2. AML without maturation (FAB M1).
   3. AML with maturation (FAB M2).
   4. AML (FAB M4).
   5. Acute monoblastic and monocytic leukemia (FAB M5a and M5b, respectively).
   6. Acute erythroid leukemia (FAB M6).
      1. Erythroleukemia (FAB M6a).
      2. Pure erythroid leukemia (FAB M6b).
   7. Acute megakaryoblastic leukemia (FAB M7).
   8. Acute basophilic leukemia.
   9. Acute panmyelosis with myelofibrosis.
   10. Myeloid (granulocytic) sarcoma.

The treatment for children with AML differs significantly from that for ALL. As a consequence, it is crucial to distinguish AML from ALL. Special histochemical stains performed on bone marrow specimens of children with acute leukemia can be helpful to confirm their diagnosis. The stains most commonly used include myeloperoxidase, PAS, Sudan Black B, and esterase. In most cases the staining pattern with these histochemical stains will distinguish AML from AMML and ALL (see below). This approach is being replaced by immunophenotyping using flow cytometry.

The use of monoclonal antibodies to determine cell-surface antigens of AML cells is helpful to reinforce the histologic diagnosis. Various lineage-specific monoclonal antibodies that detect antigens on AML cells should be used at the time of initial diagnostic workup, along with a battery of lineage-specific T-lymphocyte and B-lymphocyte markers to help distinguish AML from ALL and bilineal (as defined above) or biphenotypic leukemias. The expression of various proteins, termed cluster designations (CD), that are relatively lineage-specific for AML include CD33, CD13, CD14, CDw41 (or platelet antiglycoprotein IIb/IIIa), CD15, CD11B, CD36, and antiglycophorin A. Lineage-associated B-lymphocytic antigens CD10, CD19, CD20, CD22, and CD24 may be present in 10% to 20% of AMLs, but monoclonal surface immunoglobulin and cytoplasmic immunoglobulin heavy chains are usually absent; similarly, CD2, CD3, CD5, and CD7 lineage-associated T-lymphocytic antigens are present in 20% to 40% of AMLs.[12-14] The aberrant expression of lymphoid-associated antigens by AML cells is relatively common but generally has no prognostic significance.[12,13]

Immunophenotyping can also be helpful in distinguishing some FAB subtypes of AML. Testing for the presence of HLA-DR can be helpful in identifying APL. Overall, HLA-DR is expressed on 75% to 80% of AMLs but rarely expressed on APL. In addition, APL cases with PML/RARA were noted to express CD34/CD15 and demonstrate a heterogenous pattern of CD13 expression.[15] Testing for the presence of glycoprotein Ib, glycoprotein IIb/IIIa, or Factor VIII antigen expression is helpful in making the diagnosis of M7 (megakaryocytic leukemia). Glycophorin expression is helpful in making the diagnosis of M6 (erythroid leukemia).[16]

Chromosomal analyses of the leukemia should be performed on children with AML because chromosomal abnormalities are important diagnostic and prognostic markers.[17-19] Clonal chromosomal abnormalities have been identified in the blasts of about 75% of children with AML and are useful in defining subtypes with particular characteristics (e.g., t[8;21] with M2, t[15;17] with M3, inv[16] with M4 Eo, 11q23 abnormalities with M4 and M5, t[1;22] with M7). Leukemias with the chromosomal abnormalities t(8;21) and inv(16) are called core-binding factor leukemias; core-binding factor (a transcription factor involved in hematopoietic stem cell differentiation) is disrupted by each of these abnormalities.

Molecular probes and newer cytogenetic techniques (e.g., fluorescence in situ hybridization [FISH]) can detect cryptic abnormalities that were not evident by standard cytogenetic banding studies.[20] This is clinically important when optimal therapy differs, as in APL. Use of these techniques can identify cases of APL when the diagnosis is suspected but the t(15;17) is not identified by routine cytogenetic evaluation. The presence of the Philadelphia chromosome in children with AML most likely represents chronic myelogenous leukemia (CML) that has transformed to AML rather than de novo AML. Molecular methods are also being used to identify recurring gene mutations in adults and children with AML, and as described below, some of these recurring mutations appear to have prognostic significance.

Specific recurring cytogenetic and molecular abnormalities include:

• AML with t(8;21): In leukemias with t(8;21), the AML1 (RUNX1, CBFA2) gene on chromosome 21 is fused with the ETO gene on chromosome 8. The t(8;21) translocation is associated with the FAB M2 subtype and with granulocytic sarcomas.[21,22] Adults with t(8;21) have a more favorable prognosis than adults with other types of AML.[17,23] Most reports of recent studies describe a more favorable outcome for children with t(8;21) AML than the average outcome for all children with AML.[17,24-26]



• AML with inv(16): In leukemias with inv(16), the CBF beta gene at chromosome band 16q22 is fused with the MYH11 gene at chromosome band 16p13. The inv(16) translocation is associated with the FAB M4Eo subtype.[27] Inv(16) confers a favorable prognosis for both adults and children with AML.[17,24-26]



• AML with t(15;17): AML with t(15;17) is invariably associated with APL, a distinct subtype of AML that is treated differently than other types of AML because of its marked sensitivity to the differentiating effects of all-trans retinoic acid. The t(15;17) translocation leads to the production of a fusion protein involving the retinoid acid receptor alpha and PML.[28] Other much less common translocations involving the retinoic acid receptor alpha can also result in APL (e.g., t[11;17] involving the PLZF gene).[29] Identification of cases with the t(11;17) is important because of their decreased sensitivity to all-trans retinoic acid.[28,29]



• AML with MLL gene rearrangements: Translocations of chromosomal band 11q23 involving the MLL gene, including most AML secondary to epipodophyllotoxin,[30] are associated with monocytic differentiation (FAB M4 and M5). Outcome for patients with de novo AML and MLL gene rearrangement are generally reported as being similar to that for other patients with AML.[17,31] However, the MLL gene can participate in translocations with many different fusion partners, and the specific fusion partner may influence prognosis. For example, several reports have described more favorable prognosis for cases with t(9;11), in which the MLL gene is fused with the AF9 gene. [17,32-34]

  The t(10;11) translocation has been reported to define a group at particularly high risk of relapse in bone marrow and the central nervous system (CNS).[17,35]Some cases with the t(10;11) translocation have fusion of the MLL gene with the AF10 (MLLT10) gene on chromosome 10, with most of these cases having the FAB M5 subtype.[36] AML with t(10;11) may also have fusion of the CALM gene on chromosome 11 with the AF10 gene.[37] Based on the limited number of cases reported, prognosis appears poor for cases with t(10;11) regardless of the type of gene fusion present.[38]




• Abnormalities with chromosomes 3, 5, and 7: Chromosomal abnormalities associated with poor prognosis in adults with AML include those involving chromosome 7 (monosomy 7 , chromosome 5 (monosomy 5 and del[5q]) and the long arm of chromosome 3 (inv[3][q21q26] or t[3;3][q21q26]).[17,23] These cytogenetic subgroups are also associated with poor prognosis in children with AML, though abnormalities of the long arm of chromosomes 3 and 5 are extremely rare in pediatric patients.[23,39,40] In the past, patients with del(7q) were also considered to be at high risk of treatment failure. However, more recent reports indicate that outcome for both adults and children with del(7q) are comparable to that of other patients with AML. The presence of del(7q) does not abrogate the prognostic significance of favorable cytogenetic characteristics [e.g., inv(16), t(8;21)].[17,41,42]



• AML with t(1;22): The t(1;22)(p13;q13) translocation is restricted to acute megakaryoblastic leukemia (AMKL) and occurs in as many as one-third of AMKL cases in children.[43-45] Most AMKL cases with t(1;22) occur in infants, and the translocation is uncommon in children with Down syndrome who develop AMKL.[43,45] In leukemias with t(1;22), the OTT (RBM15) gene on chromosome 1 is fused to the MAL (MLK1) gene on chromosome 22.[46,47] Cases with detectable OTT/MAL fusion transcripts in the absence of t(1;22) have been reported, as well.[45] In the small number of children reported, the presence of the t(1;22) appears to be associated with poor prognosis, though long-term survivors have been noted following intensive therapy.[45,48]



• AML with FLT3 mutations: Presence of a FLT3 internal-tandem duplication (ITD) mutation appears to be associated with poor prognosis in adults with AML,[49] particularly when both alleles are mutated or there is a high ratio of the mutant allele to the normal allele.[50,51] FLT3-ITD mutations also occur in pediatric AML cases,[52-55] and as with adults, FLT3-ITD mutations appear to be associated with poor prognosis in children with AML.[52-56] The frequency of FLT3-ITD mutations in children appears to be lower than that observed for adults, especially for children younger than 10 years, for whom 5% to 10% of cases have the mutation (compared with approximately 30% for adults).[54,55] Activating point mutations of FLT3 have also been identified in both adults and children with AML,[50,54,57] though the clinical significance of these mutations is not clearly defined. FLT3-ITD and point mutations occur in 30% to 40% of children and adults with APL.[53,58-60] Presence of the FLT3-ITD mutation is strongly associated with the microgranular variant (M3v) of APL and with hyperleukocytosis.[53,60] It remains unclear whether FLT3 mutations are associated with poorer prognosis in patients with APL who are treated with modern therapy that includes all-trans retinoic acid.[58,59]



• RAS and tyrosine kinase receptor mutations (e.g., c-KIT): Although mutations in ras have been identified in approximately 25% of patients with AML, the prognostic significance has not been clearly shown.[61,62] Mutations in c-KIT occur in less than 5% of AML, but in up to 10% to 40% of AML with core-binding factor abnormalities.[63,64] The presence of activating c-KIT mutations in adults with this subgroup of AML appears to be associated with a poorer prognosis compared to core-binding factor AML without c-KIT mutation.[64-66] The prognostic significance of c-KIT mutations occurring in pediatric core-binding factor AML remains unclear.[63,67,68]



• GATA1 mutations: GATA1 mutations are present in most, if not all, Down syndrome children with either transient myeloproliferative disease (TMD) or AMKL.[69-72] GATA1 mutations are not observed in non–Down syndrome children with AMKL or in Down syndrome children with other types of leukemia.[71,72] GATA1 is a transcription factor that is required for normal development of erythroid cells, megakaryocytes, eosinophils, and mast cells.[73] GATA1 mutations confer increased sensitivity to cytarabine by down-regulating cytidine deaminase expression, possibly providing an explanation for the superior outcome of children with Down syndrome and M7 AML when treated with cytarabine-containing regimens.[74]



• Nucleophosmin (NPM1) mutations: NPM1 is a protein that has been linked to ribosomal protein assembly and transport as well as being a molecular chaperone involved in preventing protein aggregation in the nucleolus. Immunohistochemical methods can be used to accurately identify patients with NPM1 mutations by the demonstration of cytoplasmic localization of NPM.[75] Mutations in the NPM1 protein that diminish its nuclear localization are primarily associated with a subset of AML with a normal karyotype, absence of CD34 expression,[76] and an improved prognosis in the absence of FLT3-ITD mutations in adults and younger adults.[76-81] Preliminary studies of children with AML suggest a lower rate of occurrence of this mutation in children compared with adults with normal cytogenetics.[82,76-79,83,84] NPM1 mutations have been reported to occur in approximately 8% of pediatric patients with AML and are associated with a favorable prognosis in patients with AML characterized by a normal karyotype.[85] In this pediatric population, the presence of NPM1 mutations did not appear to abrogate the poor prognosis of having an FLT3-ITD mutation.[85]



• CEBPA mutations: Mutations in the CCAAT/Enhancer Binding Protein Alpha gene (CEBPA) occur in a subset of children and adults with cytogenetically normal AML. In adults younger than 60 years, approximately 15% of cytogenetically normal AML cases have mutations in CEBPA.[80,86] Outcome for adults with AML, with CEBPA mutations, appears to be relatively favorable and similar to that of patients with core binding factor leukemias.[80,86] The prognostic significance of CEBPA mutations in children with AML is under evaluation.



• WT1 mutations: WT1, a zinc-finger protein regulating gene transcription, is mutated in approximately 10% of cytogenetically normal cases of AML in adults.[87,88] WT1 mutation was an independent predictor of the worst disease-free survival and overall survival in adults with AML. The prognostic significance of WT1 mutations in children is under evaluation.[89]

The FAB classification of myelodysplastic syndromes (MDS) is not completely applicable to children.[90,91] In adults, MDS is divided into several distinct categories based on the presence of myelodysplasia, types of cytopenia, specific chromosomal abnormalities, and the percentage of myeloblasts.[91-94]

A modified classification schema for MDS and myeloproliferative disorders has been developed by the WHO. The primary WHO classification changes include:

• Cases with 20% to 29% blasts should be called AML, thus eliminating refractory anemia with excess blasts in transformation (RAEB-T).



• RAEB is now divided into RAEB-1 (5%–9% bone marrow [BM] blasts) and RAEB-2 (10%–19% BM blasts).



• Multilineage dysplasia will be highlighted under refractory anemia with ringed sideroblasts (RARS) or refractory anemia (RA).



• Juvenile myelomonocytic leukemia (JMML) and proliferative chronic myelomonocytic leukemia (CMML) will be under MDS/MPD (myeloproliferative disorder).



• MDS unclassified will include severe myelofibrosis.



• MDS associated with isolated del(5q) will be a separate category.



• Monocytosis (≤13,000 monocytes) will be listed under the other subtypes rather than a separate category.

RARS is rare in children. RA and RAEB are more common. The WHO classification schema has a new subgroup that includes JMML (formerly juvenile chronic myeloid leukemia), CMML, and Philadelphia (Ph) chromosome–negative CML. This group can show mixed myeloproliferative and sometimes myelodysplastic features. JMML shares some characteristics with adult CMML [96-98] but is a distinct syndrome (see below). A subgroup of children younger than 4 years at diagnosis with myelodysplasia have monosomy 7. For this subset of children, their disease is best classified as a subtype of JMML. The International Prognostic Scoring System (IPSS) is used to determine the risk of progression to AML and the outcome in adult patients with MDS. When this system was applied to children with MDS or JMML, only a blast count of less than 5% and a platelet count of more than 100 x 10⁹/L were associated with a better survival in MDS, and a platelet count of more than 40 x 10⁹/L predicted a better outcome in JMML.[99] These results suggest that MDS and JMML in children may be significantly different disorders than adult-type MDS. Older children with monosomy 7 and high-grade MDS, however, behave more like adults with MDS and are best classified that way and treated with allogeneic HSCT.[100,101] The risk group or grade of MDS is defined according to IPSS guidelines.[102] A pediatric approach to the WHO classification of myelodysplastic and myeloproliferative diseases was published in 2003; however, the usefulness of this classification has yet to be evaluated prospectively in clinical practice.[11] A retrospective comparison of the WHO classification with the category, cytology, and cytogenetics system and a Pediatric WHO adaptation for MDS/MPD, has shown that the latter two systems are better able to effectively classify childhood MDS than the more general WHO system.[103] A prospective study should be done to definitively determine the optimal classification scheme for childhood MDS/MPD.[11]

JMML is a rare leukemia that accounts for less than 1% of childhood leukemia cases.[96] JMML typically presents in young children (a median age of approximately 1 year) and occurs more commonly in boys (male to female ratio approximately 2.5:1). Common clinical features at diagnosis include hepatosplenomegaly (97%), lymphadenopathy (76%), pallor (64%), fever (54%), and skin rash (36%).[104] In children presenting with clinical features suggestive of JMML, a definitive diagnosis requires the following:[105]

Distinctive characteristics of JMML cells include in vitro hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF) and activated ras signaling secondary to mutations in various components of this pathway.[106-108] While the majority of children with JMML have no detectable cytogenetic abnormalities, a minority show loss of chromosome 7 in bone marrow cells.[97,104,109,110]

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49. Schnittger S, Schoch C, Dugas M, et al.: Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease. Blood 100 (1): 59-66, 2002.  [PUBMED Abstract]
    
    
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51. Whitman SP, Archer KJ, Feng L, et al.: Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: a cancer and leukemia group B study. Cancer Res 61 (19): 7233-9, 2001.  [PUBMED Abstract]
    
    
52. Iwai T, Yokota S, Nakao M, et al.: Internal tandem duplication of the FLT3 gene and clinical evaluation in childhood acute myeloid leukemia. The Children's Cancer and Leukemia Study Group, Japan. Leukemia 13 (1): 38-43, 1999.  [PUBMED Abstract]
    
    
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54. Meshinchi S, Stirewalt DL, Alonzo TA, et al.: Activating mutations of RTK/ras signal transduction pathway in pediatric acute myeloid leukemia. Blood 102 (4): 1474-9, 2003.  [PUBMED Abstract]
    
    
55. Zwaan CM, Meshinchi S, Radich JP, et al.: FLT3 internal tandem duplication in 234 children with acute myeloid leukemia: prognostic significance and relation to cellular drug resistance. Blood 102 (7): 2387-94, 2003.  [PUBMED Abstract]
    
    
56. Meshinchi S, Alonzo TA, Stirewalt DL, et al.: Clinical implications of FLT3 mutations in pediatric AML. Blood 108 (12): 3654-61, 2006.  [PUBMED Abstract]
    
    
57. Abu-Duhier FM, Goodeve AC, Wilson GA, et al.: Identification of novel FLT-3 Asp835 mutations in adult acute myeloid leukaemia. Br J Haematol 113 (4): 983-8, 2001.  [PUBMED Abstract]
    
    
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61. Radich JP, Kopecky KJ, Willman CL, et al.: N-ras mutations in adult de novo acute myelogenous leukemia: prevalence and clinical significance. Blood 76 (4): 801-7, 1990.  [PUBMED Abstract]
    
    
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63. Shimada A, Taki T, Tabuchi K, et al.: KIT mutations, and not FLT3 internal tandem duplication, are strongly associated with a poor prognosis in pediatric acute myeloid leukemia with t(8;21): a study of the Japanese Childhood AML Cooperative Study Group. Blood 107 (5): 1806-9, 2006.  [PUBMED Abstract]
    
    
64. Schnittger S, Kohl TM, Haferlach T, et al.: KIT-D816 mutations in AML1-ETO-positive AML are associated with impaired event-free and overall survival. Blood 107 (5): 1791-9, 2006.  [PUBMED Abstract]
    
    
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69. Groet J, McElwaine S, Spinelli M, et al.: Acquired mutations in GATA1 in neonates with Down's syndrome with transient myeloid disorder. Lancet 361 (9369): 1617-20, 2003.  [PUBMED Abstract]
    
    
70. Hitzler JK, Cheung J, Li Y, et al.: GATA1 mutations in transient leukemia and acute megakaryoblastic leukemia of Down syndrome. Blood 101 (11): 4301-4, 2003.  [PUBMED Abstract]
    
    
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72. Wechsler J, Greene M, McDevitt MA, et al.: Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome. Nat Genet 32 (1): 148-52, 2002.  [PUBMED Abstract]
    
    
73. Gurbuxani S, Vyas P, Crispino JD: Recent insights into the mechanisms of myeloid leukemogenesis in Down syndrome. Blood 103 (2): 399-406, 2004.  [PUBMED Abstract]
    
    
74. Ge Y, Stout ML, Tatman DA, et al.: GATA1, cytidine deaminase, and the high cure rate of Down syndrome children with acute megakaryocytic leukemia. J Natl Cancer Inst 97 (3): 226-31, 2005.  [PUBMED Abstract]
    
    
75. Falini B, Martelli MP, Bolli N, et al.: Immunohistochemistry predicts nucleophosmin (NPM) mutations in acute myeloid leukemia. Blood 108 (6): 1999-2005, 2006.  [PUBMED Abstract]
    
    
76. Falini B, Mecucci C, Tiacci E, et al.: Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med 352 (3): 254-66, 2005.  [PUBMED Abstract]
    
    
77. Döhner K, Schlenk RF, Habdank M, et al.: Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations. Blood 106 (12): 3740-6, 2005.  [PUBMED Abstract]
    
    
78. Verhaak RG, Goudswaard CS, van Putten W, et al.: Mutations in nucleophosmin (NPM1) in acute myeloid leukemia (AML): association with other gene abnormalities and previously established gene expression signatures and their favorable prognostic significance. Blood 106 (12): 3747-54, 2005.  [PUBMED Abstract]
    
    
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82. Chou WC, Tang JL, Lin LI, et al.: Nucleophosmin mutations in de novo acute myeloid leukemia: the age-dependent incidences and the stability during disease evolution. Cancer Res 66 (6): 3310-6, 2006.  [PUBMED Abstract]
    
    
83. Thiede C, Creutzig E, Reinhardt D, et al.: Different types of NPM1 mutations in children and adults: evidence for an effect of patient age on the prevalence of the TCTG-tandem duplication in NPM1-exon 12. Leukemia 21 (2): 366-7, 2007.  [PUBMED Abstract]
    
    
84. Cazzaniga G, Dell'Oro MG, Mecucci C, et al.: Nucleophosmin mutations in childhood acute myelogenous leukemia with normal karyotype. Blood 106 (4): 1419-22, 2005.  [PUBMED Abstract]
    
    
85. Brown P, McIntyre E, Rau R, et al.: The incidence and clinical significance of nucleophosmin mutations in childhood AML. Blood 110 (3): 979-85, 2007.  [PUBMED Abstract]
    
    
86. Marcucci G, Maharry K, Radmacher MD, et al.: Prognostic Significance of, and Gene and MicroRNA Expression Signatures Associated With, CEBPA Mutations in Cytogenetically Normal Acute Myeloid Leukemia With High-Risk Molecular Features: A Cancer and Leukemia Group B Study. J Clin Oncol : , 2008.  [PUBMED Abstract]
    
    
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88. Virappane P, Gale R, Hills R, et al.: Mutation of the Wilms' Tumor 1 Gene Is a Poor Prognostic Factor Associated With Chemotherapy Resistance in Normal Karyotype Acute Myeloid Leukemia: The United Kingdom Medical Research Council Adult Leukaemia Working Party. J Clin Oncol : , 2008.  [PUBMED Abstract]
    
    
89. Miyagawa K, Hayashi Y, Fukuda T, et al.: Mutations of the WT1 gene in childhood nonlymphoid hematological malignancies. Genes Chromosomes Cancer 25 (2): 176-83, 1999.  [PUBMED Abstract]
    
    
90. Bennett JM, Catovsky D, Daniel MT, et al.: Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 51 (2): 189-99, 1982.  [PUBMED Abstract]
    
    
91. Mandel K, Dror Y, Poon A, et al.: A practical, comprehensive classification for pediatric myelodysplastic syndromes: the CCC system. J Pediatr Hematol Oncol 24 (7): 596-605, 2002.  [PUBMED Abstract]
    
    
92. Bennett JM: World Health Organization classification of the acute leukemias and myelodysplastic syndrome. Int J Hematol 72 (2): 131-3, 2000.  [PUBMED Abstract]
    
    
93. Head DR: Proposed changes in the definitions of acute myeloid leukemia and myelodysplastic syndrome: are they helpful? Curr Opin Oncol 14 (1): 19-23, 2002.  [PUBMED Abstract]
    
    
94. Nösslinger T, Reisner R, Koller E, et al.: Myelodysplastic syndromes, from French-American-British to World Health Organization: comparison of classifications on 431 unselected patients from a single institution. Blood 98 (10): 2935-41, 2001.  [PUBMED Abstract]
    
    
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96. Aricò M, Biondi A, Pui CH: Juvenile myelomonocytic leukemia. Blood 90 (2): 479-88, 1997.  [PUBMED Abstract]
    
    
97. Passmore SJ, Hann IM, Stiller CA, et al.: Pediatric myelodysplasia: a study of 68 children and a new prognostic scoring system. Blood 85 (7): 1742-50, 1995.  [PUBMED Abstract]
    
    
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100. Kardos G, Baumann I, Passmore SJ, et al.: Refractory anemia in childhood: a retrospective analysis of 67 patients with particular reference to monosomy 7. Blood 102 (6): 1997-2003, 2003.  [PUBMED Abstract]
     
     
101. Passmore SJ, Chessells JM, Kempski H, et al.: Paediatric myelodysplastic syndromes and juvenile myelomonocytic leukaemia in the UK: a population-based study of incidence and survival. Br J Haematol 121 (5): 758-67, 2003.  [PUBMED Abstract]
     
     
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105. Pinkel D: Differentiating juvenile myelomonocytic leukemia from infectious disease. Blood 91 (1): 365-7, 1998.  [PUBMED Abstract]
     
     
106. Emanuel PD, Bates LJ, Castleberry RP, et al.: Selective hypersensitivity to granulocyte-macrophage colony-stimulating factor by juvenile chronic myeloid leukemia hematopoietic progenitors. Blood 77 (5): 925-9, 1991.  [PUBMED Abstract]
     
     
107. Tartaglia M, Niemeyer CM, Fragale A, et al.: Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet 34 (2): 148-50, 2003.  [PUBMED Abstract]
     
     
108. Loh ML, Vattikuti S, Schubbert S, et al.: Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis. Blood 103 (6): 2325-31, 2004.  [PUBMED Abstract]
     
     
109. Sieff CA, Chessells JM, Harvey BA, et al.: Monosomy 7 in childhood: a myeloproliferative disorder. Br J Haematol 49 (2): 235-49, 1981.  [PUBMED Abstract]
     
     
110. Hasle H, Aricò M, Basso G, et al.: Myelodysplastic syndrome, juvenile myelomonocytic leukemia, and acute myeloid leukemia associated with complete or partial monosomy 7. European Working Group on MDS in Childhood (EWOG-MDS). Leukemia 13 (3): 376-85, 1999.  [PUBMED Abstract]
     
     

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