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Acute Myeloid Leukemia Molecular In My PocketTM… ONCOLOGY: Acute Myeloid Leukemia • Cytogenetics Work-up Acute myeloid leukemia • Molecular genetic analysis Morphology B or T lymphoblastic Suspected acute leukemia/lymphoma leukemia Flow cytometry Mixed phenotype acute leukemia Acute Myeloid Leukemia with Recurrent Genetic Abnormalities Good prognosis Intermediate prognosis Poor prognosis **Acute promyelocytic leukemia Core Binding Factor (CBF) AML AML with t(9;11)(p21.3;q23.3); AML with t(6;9)(p23;q34.1); DEK/NUP214 • Associated with disseminated • RUNX1/RUNX1T1; t(8;21)(q22;q22.1) KMT2A/MLLT3 • Blasts with/without monocytic features intravascular coagulation (DIC) • Blasts with basophilic cytoplasm, azurophilic granules and • Often monoblasts and • Associated with basophilia and multilineage • Bilobed blasts with granules +/- Auer rods perinuclear hofs; may show pseudo-Chédiak-Higashi promonocytes dysplasia (often multiple) granules • May present with DIC, myeloid • FLT3-ITD mutations are common; may benefit • Sensitive to ATRA/arsenic trioxide • Neutrophils may show pseudo-Pelger-Huët nuclei and sarcoma, gingival hyperplasia from FLT3 inhibitors • PML/RARA; t(15;17)(q24.1;q21.2) salmon pink granules • >120 different translocations • Other variants: • Often single, long Auer rods with tapered ends involving KMT2A AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); • NUMA1/RARA; • Presence of KIT mutation and CD56 expression associated • Translocations involving MLLT1, GATA2, MECOM t(11;17)(q13.4;q21.2) with worse prognosis MLLT10, AFDN or ELL often result in • May have normal or elevated platelet counts, • NPM1/RARA; • ASXL1/2 mutations may also be seen AML, although translocations hepatosplenomegaly t(5;17)(q35.1;q21.2) involving KMT2A may also result in • Peripheral blood may include hypogranular • STAT5B/RARA; • CBFB/MYH11; inv(16)(p13.1q22) or t(16;16)(p13.1;q22) lymphoblastic leukemia neutrophils with pseudo-Pelger-Huët nuclei, t(17;17)(q21.2;q21.2) • Blasts with abnormal eosinophils (showing immature • Translocations may be subtle, giant and hypogranular platelets with bare • ZBTB16/RARA (formerly eosinophilic/basophilic granules, dense and purple-violet in requiring FISH/other molecular megakaryocytic nuclei PLZF/RARA); color) techniques for identification • Associated with increased dysplastic t(11;17)(q23.2;q21.2) • May be a subtle rearrangement only seen with FISH or RT- • MECOM overexpression is common; megakaryocytes with monolobated or bilobed • Cells with regular nuclei, many PCR worse prognosis nuclei, and multilineage dysplasia granules, absence of Auer rods, • Secondary cytogenetic abnormalities include +22 and +8 • Often associated with monosomy 7 (>50% of pelgeroid neutrophils, strong (each occurring in 10-15% of cases), del(7q) and +21 (in 5% cases), del(5q) and complex karyotypes MPO of cases) • Also associated with mutations of RAS/receptor • ZBTB16/RARA and STAT5B/RARA • KIT mutations in exons 8 and 17 found in 30-40% of cases; tyrosine kinase signalling pathways (NRAS, are ATRA resistant worse prognosis PTPN11, FLT3, KRAS, NF1, KIT) • Other mutations: NRAS (45% of cases), KRAS (13% of cases), • Other associated mutations: GATA2, RUNX1, FLT3 (14% of cases) SF3B1 “Molecular in My Pocket” reference cards are educational resources created by the Association of Molecular Pathology (AMP) for laboratory and other health care professionals. The content does not constitute medical or legal advice, and is not intended for use in the diagnosis or treatment of individual conditions. See www.amp.org for the full “Limitations of Liability” statement. AML with recurrent genetic abnormalities (cont’d) Acute myeloid leukemia with gene mutations AML (megakaryoblastic) with AML with BCR/ABL1 AML with mutated NPM1 • >70% of cases associated with normal t(1;22)(p13.3;q13.1); RBM15/MKL1 • Provisional entity • Blasts often show monocytic features karyotype; del(9q) may also be seen • Uncommon entity; may be congenital • De novo AML in patients with no evidence of • Multilineage dysplasia seen in up to 25% of • GATA2 mutations seen in 39% of cases, FLT3- • Restricted to infants and children aged <3 CML before/after therapy cases ITD in 5-9% of cases years) • Present with less splenomegaly, less • Often associated with normal karyotype • Biallelic mutation associated with good • Small and large megakaryoblasts admixed basophilia, lower cellularity, fewer dwarf • del(9q), +8 seen in 5-15% of cases prognosis with undifferentiated blasts megakaryocytes, normal M:E ratio compared • Secondary mutations include FLT3, DNMT3A, • Presence of dense fibrosis requiring with blast transformation of CML IDH1/2, KRAS, NRAS AML with mutated RUNX1 correlation with core biopsy • Most cases show the p210 fusion (most • Overall good prognosis; poorer prognosis • May be AML with minimal differentiation, • Poor prognosis commonly b2a2 and b3a2 fusions); minority with presence of FLT3-ITD +/- DNMT3A AML with maturation or show monocytic show p190 fusion features • Associated with -7, +8 and complex AML with biallelic mutation of CEBPA • Mutations may occur with +8 and +13 karyotypes • No distinct morphologic features (usually • Other associated mutations : ASXL1, KMT2A • May be associated with NPM1 and FLT3-ITD , have features of AML with/without partial tandem duplication, FLT3-ITD, IDH1 loss of IKZF1 and CDKN2A and cryptic maturation) R132, IDH2 R140 and R172, SRSF2, EZH2 and deletions in IGH and TRG genes (not seen in • Higher expression of HLA-DR, CD7 and CD15 STAG2 blast transformation of CML) • Presence of biallelic CEBPA should raise • Subset of these patients have germline possibility of germline mutation RUNX1 mutations; assess family history • Show poor prognosis AML with myelodysplasia-related changes Therapy-related myeloid neoplasms Other Diagnosis requires: MDS-defining cytogenetic abnormalities • Occurs as a complication of cytotoxic (e.g. Myeloid/Lymphoid Neoplasms associated with • >20% blasts (blood/bone marrow) • Complex karyotype (>3 abnormalities) alkylating agents, topoisomerase II Eosinophilia • Either: History of MDS or MDS/MPN OR MDS- • Unbalanced abnormalities inhibitors) and/or radiotherapy for • PDGFRA rearrangement (often related cytogenetic abnormality OR • -7 or del(7q) neoplastic/non-neoplastic disorders del(4)(q12q12); FIP1L1/PDGFRA) multilineage dysplasia (>50% dysplasia in >2 • del(5q) or t(5q) • May also be associated with antimetabolites • PDGFRB rearrangement (often lineages) • Isochromosome 17q or t(17q) (thiopurines, mycophenolate mofetil, t(5;12)(q31~33;p12) ;ETV6/PDGFRB) • Absence of prior cytotoxic or radiation • -13 or del(13q) fludarabine) and antitubulin agents • FGFR1 rearrangement (various partners) therapy for unrelated disease OR AML- • del(11q) (vincristine, vinblastine, vindesine, • t(8;9)(p22;p24.1);PCM1/JAK2 defining recurrent cytogenetic abnormality • del(12p) or t(12p) paclitaxel, docetaxel), hydroxyurea, L- • May be associated with mutations of U2AF1, • idic(X)(q13) asparagine, and purine analogues) Myeloid Neoplasms with Germline ASXL1, TP53 (latter two mutations worsen • Balanced abnormalities • Associated with abnormal karyotype, most Predisposition prognosis) • t(11;16)(q23.3;p13.3) often del(5q), -7, del(7q) in >70% of cases • AML with germline CEBPA mutation • t(3;21)(q26.2;q22.1) • >80% of cases with del(5q) have TP53 • Myeloid neoplasm with germline DDX41 • t(1;3)(p36.3;q21.2) mutations or losses with del(17p) or -17 mutation • t(2;11)(p21;q23.3) • 20-30% of cases have balanced • Associated with platelet disorders • t(5;12)(q32;p13.2) translocations including t(15;17) and inv(16) • RUNX1, ANKRD26, ETV6 mutations • t(5;7)(q32;q11.2) • Mutated genes of unknown significance • Associated with other organ dysfunction • t(5;17)(q32;p13.2) include TET2, PTPN11, IDH1/2, NRAS, and • GATA2 mutation • t(5;10)(q32;q21) FLT3 • JMML type mutations • t(3;5)(q25.3;q35.1) • Poor prognosis Prepared by the Association for Molecular Pathology Training and Education Committee Revised 10/19 For more educational resources, see: www.amp.org/AMPEducation.
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