Leukemia-Acute
Last revised 13 March 2008
Last major update January 2008
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Table of Contents for Leukemia-Acute chapter
Acute leukemia: general
AML: general, classification
AML recurrent genetic abnormalities: t(8;21), inv(16) or t(16;16), APL with t(15;17), APL with t(V;17), APL-therapy related, 11q23 abnormalities, FLT3 mutations, t(6;9), multilineage dysplasia, therapy related
AML not otherwise categorized: minimally differentiated, without maturation, with maturation, M3, myelomonocytic, monoblastic and monocytic, erythroid, megakaryoblastic, CD13/CD33 negative, basophilic, myeloid sarcoma, acute panmyelosis with myelofibrosis, with Philadelphia chromosome, with pseudo Chediak-Higashi anomaly, hypocellular
ALL: general, WHO classification, with eosinophilia
PreB ALL: general, t(9;22), t(v;11q23), t(1;19), t(12;21), hyperdiploidy, hypodiploidy, mature B cell ALL/Burkitt’s
Other ALL: preT, bilineal, biphenotypic
See also Chronic leukemia topics in other chapters:
B cell leukemias: chronic lymphocytic, hairy cell, preB lymphoblastic, prolymphocytic leukemia, leukemic phase of mantle cell lymphoma
T/NK cell leukemias: NK cell, adult T cell, preT lymphoblastic, T cell large granular, T cell prolymphocytic, Sezary syndrome
Myelodysplastia / myeloproliferative disorders: chronic myelomonocytic (CMML), juvenile myelomonocytic, chronic myeloid (CML), chronic neutrophilic, chronic eosinophilic
Bone chapter: plasma cell leukemia
Primary references for Leukemia-Acute chapter
American Journal of Clinical Pathology (AJCP) [free full text and no registration after 1 year]; January 1997 to January 2008
American Journal of Surgical Pathology (AJSP); August 1979 to January 2008
Archives of Pathology and Laboratory Medicine (Archives) [always free full text and no registration]; January 1997 to December 2007
Biomed Central [always free full text and no registration]; 1 March 1997 to 3 January 2008
Human Pathology (Hum Path); January 1997 to January 2008
Modern Pathology (Mod Path) [free full text and no registration after 1 year]; January 1988 to January 2008
Rosai, J: Ackerman’s Surgical Pathology (9th Ed), Mosby, 2004
Sternberg, S: Diagnostic Surgical Pathology (4th Ed); Lippincott Williams & Wilkins, 2004
Brunning: Tumors of the Bone Marrow (AFIP Atlas of Tumor Pathology, Series 3, Vol 9, 1994)
Websites (images): ASH image bank
Journal search terms: “leukemia” and each topic below
Please refer to these primary references for more detailed discussions and photographs
Acute leukemia
“Acute” because cells are immature (usually blasts) compared to mature hematopoietic cells in chronic leukemias
Acute leukemias also tend to progress rapidly without treatment, compared to indolent behavior of chronic leukemias
Ionizing radiation is only definite environmental risk factor (Environ Health Perspect 2007;115:138)
Course of disease not affected by pregnancy (Cancer 2005;104:110)
Initial diagnosis usually based on blood counts and blood smear
Bone marrow examination (biopsy and smears) is necessary to confirm diagnosis and to obtain material for special studies
Bone marrow biopsy is important to assess cellularity and monitor post-treatment changes
Cytogenetics and molecular studies are required to classify and provide prognostic information
Before making a diagnosis, review clinical information, all pathology material and special studies
Immunostains should be ordered in panels (with multiple antigens) since aberrant antigen expression is common
Common lymphoid immunostains: TdT, T cell - CD2, CD3 (cytoplasmic), CD5, CD7; B cell - HLA-DR, CD10, CD19, CD22
Common myeloid immunostains: CD13, CD14, CD15, CD33, CD36, CD61, CD64
Micro: bone marrow usually markedly hypercellular with replacement of normal cells; myelofibrosis relatively common; marrow is rarely hypocellular resembling aplastic anemia, but most cells are blasts
Post-treatment: initially hypocellular with necrosis, proteinaceous debris, dilated sinuses and increased reticulin; regeneration begins after 1-2 weeks; may be difficult to differentiate residual disease (tumor cells in no specific locations) from regenerating marrow (promyelocytes are perivascular and endosteal), particularly in acute promyelocytic leukemia; may be granulomas associated with microorganisms
AML
Acute myeloid leukemia (AML) - general
Also called acute myelogenous leukemia
Neoplastic proliferation of hematopoietic precursor cells, causing excessive myeloblasts and other immature myeloid cells
Malignant cells replace bone marrow, may infiltrate spleen, liver and lymph nodes and circulate in bloodstream
Usually less nodal involvement than ALL
80% of adult leukemia but only 20% of childhood leukemia
Neoplastic blasts have normal proliferation rates but reduced maturation rates compared to normal blasts
Risk factors: most patients have none; Down’s syndrome, Bloom’s syndrome, Fanconi’s anemia, neurofibromatosis, benzene exposure, radiation, alkylating agents, type II topoisomerase inhibitors
Symptoms: due to replacement of normal bone marrow cells by blasts; fatigue (due to anemia), fever and opportunistic infections (due to neutropenia), mucosal and cutaneous bleeding (due to thrombocytopenia), tissue infiltration with myelomonocytic, monocytic and monoblastic leukemia, including gingival hyperplasia and leukemia cutis (monocytes tend to infiltrate); sternal tenderness (due to bone marrow expansion); neurological symptoms (due to CNS infiltration)
Laboratory: 50% have WBC > 10,000, > 100,000 in 20%; due to circulating blasts and other immature myeloid cells; in aleukemic leukemia, peripheral blood lacks blasts, and must examine bone marrow
Favorable prognostic factors: young patients, rapid response to chemotherapy, see favorable cytogenetics below
Unfavorable prognostic factors: under age 2 or older than age 60, marked leukocytosis at diagnosis, history of myelodysplastic syndrome, FLT3 mutations (Blood 2006;108:3654, Blood 2002;99:4326)
Treatment: chemotherapy cures 10-30% (induction, consolidation, maintenance phases), allogeneic bone marrow transplantation cures 45-65%; 5 year survival only 20% in adults, 50% in children (Oncologist 2007;12:341)
Diagnosis: examination of blood, marrow smears and cytochemical stains is usually sufficient; immunostains may be required for poorly differentiated leukemia
Peripheral smear: anisopoikilocytosis (variation in size and shape of red blood cells), nucleated red cells, neutropenia, thrombocytopenia, hypogranular and hyposegmented neutrophils, large atypical platelets
Micro-smears: myeloblasts are usually larger than lymphoblasts of ALL; cytoplasm is more abundant, with fine azurophilic granules and Auer rods (abnormal crystallized azurophilic granules, particularly in promyelocytic leukemia); delicate nuclear chromatin with 1-4 prominent nucleoli; often dysplastic, maturing myeloid cells
Acute myeloid leukemia (AML) - general - continued
Micro-biopsy: usually markedly hypercellular with immature appearing cells but no trilinear maturation; by definition, at least 20% blasts; mitotic activity common; may have myelofibrosis; see descriptions of various subtypes
type I myeloblasts: no cytoplasmic granules, nucleus is large with delicate chromatin and prominent nucleolus
type II myeloblasts: 15-20 delicate cytoplasmic granules
type III myeloblasts: > 15-20 cytoplasmic granules, but otherwise has features of a blast cell
Micro images: type I myeloblasts #1; #2; type II myeloblasts; type III myeloblasts #1; #2
Micro images: two myeloblasts each have a single prominent Auer rod; Auer rod in neutrophil
Cytogenetics: 90% have chromosomal abnormalities; de novo leukemia often has balanced translocations, but therapy related or post-myelodysplasia leukemia often has deletions or monosomy 5 or 7 without translocations
Favorable cytogenetics: inv(16)(p13;q22), t(8;21)(q22;q22)
Intermediate cytogenetics: t(15;17)(q22;q12), +8, t(6;9)(p23;q34), t(9;11)(p22;q23) in children, normal cytogenetics
Unfavorable cytogenetics: -7, -5, del 7q, t(11q23), inv(3q), t(9;22), complex abnormalities, post-chemotherapy or post-radiation therapy
Enzyme cytochemistry: positive for myeloperoxidase (Mod Path 1991;4:733), Sudan Black B, chloroacetate esterase (stains lysosomes in granulocytes); variable for acid phosphatase; M4/M5 are positive for nonspecific esterase (alpha naphthyl butyrate esterase), M5/M6/M7 are positive for PAS
alpha-naphthyl acetate esterase (ANAE): also called modified nonspecific esterase; stains some T cells (Klin Lab Diagn 1993;6:38) and monocytic cells (Leuk Res 1998;22:25), but not erythroid cells
alpha-naphthyl butyrate esterase: also called nonspecific esterase; stains monocytes and some T cells (J Exp Med 1981;153:182)
chloroacetate esterase: also called specific esterase, naphthol AS-D chloroacetate esterase, Leder stain; stains granulocytes and mast cells, but not monocytes or lymphocytes
Positive stains: myeloid markers (CD13, CD14, CD15, CD33, CD36), CD99 (43% of AML, 55% of chloromas, Mod Path 2000;13:452); often expresses B cell antigens CD20, CD7, PAX5, OCT2 or BOB.1 (AJCP 2006;126:916); VEGF expression varies by subtype (AJCP 2003;119:663)
Negative stains: CD10
Immunohistochemistry compared with flow cytometry: CD34 has similar findings, CD15 and CD117 are more sensitive by flow, myeloperoxidase is more sensitive by immunohistochemistry (Archives 2001;125:1063)
DD: reactive process (growth factor treatment causes increased blasts), transient myeloproliferative disorder of newborns resembles AML-M7, ALL, myelodysplastic syndrome
References: eMedicine, Wikipedia, US National Cancer Institute
French-American-British (FAB) classification system was used from 1976 to 2001, divided AML into M0-M7 (Br J Haematol 1976;33:451)
WHO classification (2001) requires only 20% of blasts in bone marrow or blood to diagnose AML (was 30% under FAB), which eliminates myelodysplastic category of “refractory anemia with excess blasts in transformation” (Blood 2002;100:2292)
WHO classification also separates out AML “with recurrent genetic abnormalities”, which have distinct clinical features
Acute myeloid leukemias with recurrent genetic abnormalities
- AML with t(8;21)(q22;q22) (AML1/ETO)
- AML with inv(16)(p13q22) or t(16;16)(p13;q22) (CBFβ/MYH11)
- Acute promyelocytic leukemia (AML with t(15;17)(q22;q12) (PML/RARα) and variants
- AML with 11q23 (MLL) abnormalities
Acute myeloid leukemia with multilineage dysplasia
Acute myeloid leukemia and myelodysplastic syndrome, therapy related
- Alkylating agent related
- Topoisomerase II inhibitor related
Acute myeloid leukemia not otherwise categorized
- AML minimally differentiated (M0)
- AML without maturation (M1)
- AML with maturation (M2)
- Acute myelomonocytic leukemia (M4)
- Acute monoblastic and monocytic leukemia (M5a and M5b)
- Acute erythroid leukemia (M6)
- Acute megakaryoblastic leukemia (M7)
- Acute basophilic leukemia
- Acute panmyelosis with myelofibrosis
- Myeloid sarcoma
Acute leukemia of ambiguous lineage
- Undifferentiated acute leukemia
- Bilineal acute leukemia
- Biphenotypic acute leukemia
References: Table of contents in WHO tumor “Blue Book” (book is out of print, new version [4th edition] planned July 2008)
AML with recurrent genetic
abnormalities
Also called AML1-ETO leukemia
Translocation produces fusion product of ETO gene on #8q22 and AML1 gene on #21q22
5-10% of AML, 33% of cases of AML-M2 (AML with maturation); most common type of childhood AML
AML1-ETO may facilitate accumulation of genetic alterations by suppressing endogenous DNA repair (Blood 2007 Nov 1 [Epub ahead of print])
Additional mutations are required for leukemogenesis (Proc Natl Acad Sci USA 2000;97:7521)
Frequently associated with additional chromosomal translocations which may influence prognosis (Zhonghua Nei Ke Za Zhi 2006;45:918)
Favorable prognosis in adults, although KIT activating mutations confer poorer prognosis
Classify as AML even if initial blast count is < 20%
RT-PCR and cytogenetics for detection both have limitations (J Clin Oncol 2001;19:2482)
Variant t(8;21): similar clinical features, morphology and immunostaining as classic t(8;21) cases (AJCP 2006;125:267)
Case reports: with occult mastocytosis (J Clin Pathol 2004;57:324)
Micro: resembles AML-M2 (AML with maturation) - large blasts, abundant basophilic cytoplasm, frequent large Auer rods and chunky cytoplasmic granules, perinuclear hofs, neutrophil dysplasia; trilineage dysplasia present in therapy related cases (AJCP 2002;117:306); peripheral blood contains smaller blasts
Micro images:
bone marrow smear (Wright-Giemsa): myelocytes have abundant cytoplasm with prominent granulation, one myeloblast (slightly left and below center) has prominent Auer rod; myeloblasts with Auer rods, promyelocytes and other mature cells; large blast cells with abundant basophilic cytoplasm, often numerous azurophilic granules, may have large granules (pseudo Chediak-Higashi granules), often Auer rods, accompanied by promyelocytes, myelocytes and mature granulocytes with variable dysplasia; various images #1; #2-H&E and stains
Positive stains: CD19 (75-93%) and CD56 (82%) (aberrant expression compared to classic AML M2, AJCP 2007;128:550); also PAX5/BSAP (usually weak) and Oct2 (75%, AJCP 2006;126:235); high levels of CD34 and myeloperoxidase and low levels of CD33 by flow cytometry (Mod Path 2004;17:1211)
Negative stains: CD20, CD22, CD79a
Molecular: AML1 gene also called RUNX1, encodes core binding factor alpha
Cytogenetic images: t(8;21) with abnormal chromosomes on right, and breakpoints at arrowheads; various images; variants
AML with inv(16)(p13;q22) or t(16;16)(p13;q22)
Also called M4Eo
8% of adult AML, 25% of acute myelomonocytic leukemia (AML M4) cases
Associated with more frequent hepatosplenomegaly, lymphadenopathy and granulocytic sarcoma than AML in general
Longer median survival than other AML (AJCP 2003;119:672); complete remission rates are 76% to 92%
If translocation present, consider as AML even if initial blast count is < 20%
FISH recommended if suggestive cell morphology but negative cytogenetics (J Mol Diagn 2004;6:271)
Poorer prognostic factors are high initial WBC count for complete response and age > 35 years for disease free survival (Blood 2003;102:462)
Peripheral blood: monocytosis, high blast counts
Micro: usually AML M4 (acute myelomonocytic leukemia) features plus marrow eosinophilia with dysplastic eosinophils containing large basophilic staining granules in addition to usual eosinophilic granules; usually >10% dysplastic forms in at least one lineage (AJCP 2003;120:236)
Micro images:
bone marrow smears (Wright-Giemsa): eosinophil precursors show prominent basophilic staining granules #1; #2; H&E, cytogenetics and FISH; immature cells with folded, monocytoid nuclei mixed with abnormal eosinophils (arrow) containing large basophilic granules and more normal eosinophil granules; various eosinophil precursors; various images #1; #2; #3; #4; #5 (some images associated with cytogenetic changes); H&E, RT-PCR and FISH
Virtual slides: bone marrow smear-AML with inv(16)
Positive stains: granules are positive for chloroacetate esterase and nonspecific esterase; high Ki-67, CBFbeta-SMMHC (nuclear stain with microgranular or fine-speckled pattern, AJSP 2006;30:1436)
Molecular: inversion(16) or t(16;16)(p13;q22) are due to breaks in smooth muscle myosin heavy chain gene (SMMHC) producing MYH11 at 16p13 and core binding factor beta (CBF-beta) gene at 16q22, creating CBF-beta - MYH11 protein (Science 1993;261:1041, Proc Natl Acad Sci USA 1998;95:11863); multiple fusion transcripts exist (J Mol Diagn 2004;6:22); fusion transcripts appear to upregulate NF-kappaB signaling pathway (Mod Path 2007;20:811)
Molecular images: two G banded chromosome 16 pairs show pericentric inversion at #16, arrowheads point to breakpoints on abnormal chromosome; diagram; karyotype
Acute promyelocytic leukemia (APL) with t(15;17)(q22;q12)
Either hypergranular (this section) or microgranular (section below)
8% of AML cases, 15% of adult AML
Formerly called AML M3
Median age 35-40 years
Decreased WBC count at presentation with abnormal promyelocytes; usually severe disseminated intravascular coagulation (DIC) and hemorrhage before or during induction chemotherapy, which may cause early death; organomegaly or extramedullary disease is unusual
Rarely has skin involvement, detected with FISH (Mod Path 2005;18:1569)
Criteria for diagnosis: most cells (>50%) are abnormal promyelocytes with heavy cytoplasmic granulation, often reniform nucleus; cells with multiple Auer bodies usually present
Note: if t(15;17) present, diagnose as AML even if initial blast count is < 20%
Prognostic factors: in children, age < 10 years is favorable (Cancer 2006;106:2495)
Case reports: 45 year old man with fatigue
Treatment: (1) all trans retinoic acid (ATRA) causes neoplastic promyelocytes to rapidly differentiate into bizarre maturing neutrophils, but patients eventually relapse; (2) arsenic trioxide (ATO) for ATRA-refractory patients; induces differentiation at low doses, marrow necrosis at high doses (Mod Path 2000;13:954); (3) combination chemotherapy required for sustained remissions (Hematology Am Soc Hematol Educ Program 2006;147)
Survival: excellent if DIC and hemorrhage are adequately controlled; excellent in adults with complete remission
Micro: most cells are hypergranular promyelocytes (abundant cytoplasm, round/oval and frequently eccentric nuclei with occasional clefts or indentations, moderately condensed chromatin, indistinct nucleoli) with heavy red/purple cytoplasmic granulation that may obscure nuclear borders; 90% have multiple Auer rods in some cells, which may be intertwined (“faggot” cell-word is derived from Middle English/Old French term for bundle of twigs, sticks, or branches bound together); reniform (kidney shaped) nucleus; may have basophilic cytoplasm, <20% myeloblasts
post-treatment: may be difficult to differentiate residual disease (promyelocytes not in any particular location) from regenerating marrow (promyelocytes are perivascular and endosteal)
Acute promyelocytic leukemia (APL) with t(15;17)(q22;q12) - continued
Micro images:
bone marrow smears (Wright-Giemsa): abundant azurophilic granules #1, also two microgranular promyelocytes with basophilic cytoplasm and lobulated nuclei; #2; numerous Auer rods in bundles
bone marrow biopsy: bone marrow is almost completely replaced by promyelocytes with abundant cytoplasm, oval/round nuclei that are often eccentrically located, with occasional indentations/clefts, somewhat condensed chromatin and indistinct nucleoli; promyelocytes are relatively uniform with abundant cytoplasm containing dense azurophilic granules and multiple Auer rods, nuclei are round, oval and lobulated
treatment related: before and after arsenic trioxide; post-chemotherapy smear shows single “faggot” cell with numerous Auer rods in bundles
other sites: skin infiltration-various H&E and FISH
stains: CD99 (figures 3C/3D); H&E and CD99 (fig A1/A2)
Positive stains: CD9, CD11a, CD11b (post-treatment only-ATRA: Archives 2003;127:e4 or arsenic trioxide: Mod Path 2000;13:954), CD13, CD33, CD79a (86% but varies by clone, AJCP 2007;128:306), myeloperoxidase (strong), CD2 (23%), CD64 (27%), HLA-DR (9%); variable CD34, CD71, CD99
Negative stains: CD11b (but post-treatment is positive), CD11c (AJCP 1998;109:211), CD14, CD34, CD36, CD41, CD61, glycophorin A
Molecular: t(15;17) translocation not found in other AML subtypes; breakpoints at PML gene on #15q22 and retinoic acid receptor alpha (RARa) gene on #17q21; hybrid mRNA produces abnormal retinoic acid receptor that blocks myeloid differentiation
Cases without Auer rods usually have additional chromosomal abnormalities besides t(15;17) (AJCP 1999;112:113)
Cytogenetic images: t(15;17)-arrowheads at breakpoints on abnormal chromosomes; karyotype
Molecular images: FISH - negative and positive control of t(15;17)
EM: Auer rods have tubular substructure, markedly dilated endoplasmic reticulum, stellate complexes of rough ER, nucleus has dispersed chromatin and prominent nucleolus
EM images: cytoplasm has numerous dense granules and several Auer rods, nucleus has dispersed chromatin and prominent nucleolus; cross section of Auer rod shows characteristic tubular structure
References: Atlas of Genetics and Cytogenetics
Microgranular variant of acute promyelocytic leukemia
Formerly called AML-M3v
Note: “variant” APL without further description may mean microgranular variant or cytogenetic variant (see below)
Peripheral blood white blood count usually elevated, in contrast to hypergranular form
Diagnosis: cytogenetics recommended, because other AML cases may appear similar (AJCP 2002;117:651)
Case reports: 5 year old girl with Down’s syndrome (J Med Case Reports 2007;1:147), post-chemotherapy with atypical breakpoints for translocation (Cancer Genet Cytogenet 2002;138:143), occuring after untreated essential thrombocythemia (Am J Hematol 2002;71:114)
Micro: leukemic cells have fewer and smaller cytoplasmic granules, usually multiple Auer rods but less than classic (hypergranular) promyelocytic leukemia; nuclei is folded, convoluted, markedly irregular
Micro images: promyelocytes have abundant fine, azurophilic cytoplasm with variable size and basophilia, markedly lobulated and invaginated nuclei #1; #2; small hyperbasophilic promyelocytes with prominent cytoplasmic budding, most cells have sparsely granular cytoplasm and lobulated nuclei #1; #2
Positive stains: CD34 (more common than hypergranular variant, Haematologica 2006;91:311), CD13, CD33, myeloperoxidase (strong), usually CD2 (Leukemia 1995;9:1461)
Molecular: associated with FLT-3 aberrations (Br J Haematol 2004;125:463) and different gene expression profile than hypergranular APL (Genes Chromosomes Cancer 2005;43:113)
EM: stellate array of endoplasmic reticulum is characteristic
EM images: smaller granules than hypergranular variant, granules are more uniform in size, endoplasmic reticulum is prominent; small granules and stellate array of endoplasmic reticulum
DD: other AML (AJCP 2002;117:651)
References: Blood 1980;55:253
Acute promyelocytic leukemia with t(V;17)(V;q12)
Note: “variant” APL without further description may mean microgranular (morphologic) variant or cytogenetic variant other than t(15;17)
Uncommon, involves retinoic acid receptor alpha on #17 but not PML gene on #15
t(11;17) is most common
DIC common; may NOT respond to all-trans retinoic acid; may be more aggressive than classic acute promyelocytic leukemia (Blood 1995;85:1083)
Recommended to combine cytogenetics, FISH and molecular biology to document presence / absence of PML-RARalpha fusion gene in complex cases (Cancer Genet Cytogenet 2005;159:69)
Case reports: with PRKAR1A gene (Blood 2007;110:4073), t(17;20) masking t(15;17) (Cancer Genet Cytogenet 2006;168:73)
Micro: features are intermediate between hypergranular acute promyelocytic leukemia (M3) and acute leukemia with maturation (M2) - most cells have many granules, usually no Auer rods, regular nuclei but increased pseudo Pelger-Huet cells
Micro images: cells with many granules, no Auer rods, regular nuclei
Molecular: involves RAR alpha and either PLZF (11q23), NUMA (11q13), NPM (5q31) or STAT5b genes (Leukemia 2002;16:1927)
DD: t(11;17) may resemble AML with 11q23 abnormality (Cancer Genet Cytogenet 2005;159:168)
References: Atlas of Genetics and Cytogenetics-t(11;17)
Acute promyelocytic leukemia-therapy related
Not a WHO diagnosis
Prior tumor is usually breast carcinoma, other solid tumor or non-Hodgkin’s lymphoma, treated with radiation or chemotherapy (J Clin Oncol 2003;21:2123)
Usually develops within 3 years, with no preleukemic phase
Mitoxantrone and etoposide or its metabolites stimulate topoisomerase II to cleave different sites in PML and RARA (N Engl J Med 2005;352:1529)
Case reports: microgranular variant developing post-chemotherapy for breast cancer (Cancer Genet Cytogenet 2002;138:143), post-radioactive iodine for thyroid cancer (J BUON 2007;12:129), developing post-chemotherapy in 8 year old girl with non Hodgkin’s lymphoma (J Pediatr Hematol Oncol 2004;26:427)
Micro: classic findings of APL plus dyserythropoiesis and dysmegakaryopoiesis
Molecular: t(15;17)(q22;q12), often with additional abnormalities; PML-RARa in most cases; FLT-3 gene mutations in 42%
References: AJCP 2005;123:840
AML with 11q23 (MLL) abnormalities
3-5% of AML (Anticancer Res 2005;25:1931)
Usually children or young adults
Present in high percentage of topo II inhibitor, therapy related AML (Blood 2003;102:2395); also ALL and biphenotypic leukemia
More than 50 chromosomal loci have been identified as 11q23 partners, but most common are t(9;11)(p21;q23) [AF9-MLL] and t(4;11) [AF4-MLL]
FISH is more sensitive than conventional cytogenetics in detecting MLL; may also detect 11q22-25 rearrangements that are MLL negative (AJCP 2004;122:298)
PCR is more sensitive than conventional cytogenetics in detecting MLL/ENL [t(11;19)] fusion transcripts (AJCP 2007;127:24)
Typically poor prognosis
MLL partial tandem duplication: present in 93% of normal cord blood samples at low levels (Leuk Res 2006;30:1091); associated with normal karyotype or trisomy 11; typically poor prognosis in AML (Br J Haematol 2006;135:438), but recent study showed similar outcome (Blood 2007;109:5164)
Micro: blasts resemble monoblasts, monocytes or myelomonocytes (AML M4, M5)
Positive stains: nonspecific esterase
Molecular: involves MLL-mixed lineage or myeloid/lymphoid leukemia gene, present in both AML and ALL; is also called HTRX1, HRX and ALL1; translocations occur in AML (intermediate prognosis) and ALL (poor prognosis, Blood Cells Mol Dis 2007 Sep 28 [Epub ahead of print])
Molecular images: partner genes; diagram of MLL/ALL1 duplication
Cytogenetics images: t(4;11)(q21;23) in bilineal leukemia
References: OMIM 159555, Atlas of Genetics and Cytogenetics
Not a WHO diagnosis
Mutations of FMS-like tyrosine kinase 3 (FLT3) occur in 20-30% of de novo AML
Most frequent molecular abnormality in AML
Usually peripheral leukocytosis and normal cytogenetics
Mutations include internal tandem duplication/juxtamembrane domain (ITD) and tyrosine kinase domain (TKD)
FLT3-ITD associated with poor prognosis (Blood 2002;100:1532), FLT3-TKD doesn’t affect prognosis (