Acute Myeloid Leukemia o a tumor of hematopoietic progenitors o caused by acquired oncogenic mutations that impede differentiation, leading to the

accumulation of immature myeloid blasts in the marrow. o The arrest in myeloid development leads to marrow failure o AML peaks after 60 years of age o Classification. o AML WITH GENETIC ABERRATIONS AML with t(8;21)(q22;q22); CBF/ETO fusion gene (MCQ) Favorable prognosis FAB -M2 (MCQ) Full range of myelocytic maturation Auer rods easily found (MCQ) abnormal cytoplasmic granules AML with inv(16)(p13;q22); CBF/MYH11 fusion gene (MCQ) Favorable prognosis M4eo Myelocytic and monocytic differentiation abnormal eosinophilic precursors with abnormal basophilic granules (MCQ) AML with t(15;17)(q22;11-12); RAR/PML fusion gene(MCQ) Intermediate prognosis M3, M3v Numerous Auer rods, often in bundles within individual progranulocytes (MCQ) primary granules usually very prominent in M3 subtype high incidence of DIC (MCQ) AML with t(11q23;v); diverse MLL fusion genes Poor prognosis M4, M5 AML with normal cytogenetics and mutated NPM Favorable prognosis o AML WITH MDS-LIKE FEATURES With prior MDS Poor prognosis AML with multilineage dysplasia Poor prognosis AML with MDS-like cytogenetic aberrations Poor prognosis Associated with 5q-, 7q-, 20q-aberrations (MCQ) o AML, THERAPY-RELATED Very poor prognosis If following alkylator therapy or radiation therapy 2- to 8-year latency period

MDS-like cytogenetic aberrations (e.g., 5q-, 7q-) (MCQ) if following topoisomerase II inhibitor (e.g., etoposide) therapy, 1 to 3-year latency translocations involving MLL (11q23) o AML, NOT OTHERWISE SPECIFIED AML, minimally differentiated - M0 AML without maturation - M1 AML with myelocytic maturation- M2 AML with myelomonocytic maturation- M4 AML with monocytic maturation -M5a, M5b AML with erythroid maturation -M6a, M6b AML with megakaryocytic maturation- M7 most common AML in Down syndrome (MCQ) often accompanied by marrow fibrosis(MCQ) o Morphology. The diagnosis of AML is based on the presence of at least 20% myeloid blasts in the bone marrow Myeloblasts have delicate nuclear chromatin two to four nucleoli more voluminous cytoplasm than lymphoblasts The cytoplasm often contains fine, peroxidasepositive azurophilic granules. (MCQ) Auer rods, are present in many cases(MCQ) distinctive needle-like azurophilic granules, (MCQ) they are particularly numerous in AML with the t(15;17) (acute promyelocytic leukemia) (MCQ) Monoblasts have folded or lobulated nuclei lack Auer rods are nonspecific esterase-positive(MCQ) Why is a bone marrow examination is essential in pancytopenic patients ? (MCQ) to exclude acute leukemia Occasionally, blasts are entirely absent from the blood (aleukemic leukemia). o Cytogenetics. Cytogenetic analysis has a central role in the classification of AML. AMLs arising de novo in younger adults commonly associated with balanced chromosomal translocations, particularly t(8;21), inv(16), and t(15;17) (MCQ) AMLs following MDS or exposure to DNA-damaging agents (such as chemotherapy or radiation therapy) often have deletions or monosomies involving chromosomes 5 and 7 (MCQ)

usually lack chromosomal translocations. The exception to this rule is AML occurring after treatment with topoisomerase II inhibitors, which is strongly associated with translocations involving the MLL gene on chromosome 11q23. AML in the elderly more likely to be associated with bad aberrations, such as deletions of chromosomes 5q and 7q. (MCQ) o Molecular Pathogenesis. Many recurrent genetic aberrations seen in AML disrupt genes encoding transcription factors that are required for normal myeloid differentiation. t(8;21) and inv(16), (MCQ) o disrupt the CBF1 and CBF1 genes, respectively. o CBF1 and CBF1 genes encode polypeptides that bind one another to form a CBF1/CBF1 transcription factor that is required for normal hematopoiesis. t(8;21) and the inv(16) (MCQ) o create chimeric genes encoding fusion proteins that interfere with the function of CBF1/CBF1 o block the maturation of myeloid cells o mutated tyrosine kinases collaborate with transcription factor aberrations to produce AML. AML with the t(15;17), acute promyelocytic leukemia(MCQ) o t(15;17) creates yet another fusion gene that encodes a part of the retinoic acid receptor- (RAR) fused to a portion of a protein called PML (after the tumor). (MCQ) o What is normal RAR function ? In the presence of physiologic amounts of retinoic acid, normal RAR interacts with other transcription factors to activate genes that are needed for granulocytic differentiation o What happens with PML-RAR fusion protein ? (MCQ) However, the PML-RAR fusion protein interacts instead with transcriptional repressors, which results in an inhibition of granulocytic maturation o AMLs with the t(15;17) also have frequent activating mutations in FLT3(MCQ) What is FLT3 ?

FLT3 is a receptor tyrosine kinase (MCQ) It transmits signals that increase cellular proliferation and survival. o Why is aberrant tyrosine kinase activation is a common and universal feature of AML. FLT3 mutations are found in Acute Promyelocytic (M3) type AML FLT3 mutations are found in of AML associated with NPM (nucleophosmin) mutations activating mutations in tyrosine kinase receptor, c-KIT, are found in about 25% of AMLs associated with the inv(16) or the t(8;21) (MCQ) Tumors with t(15;17) translocation respond to pharmacologic doses of all-trans retinoic acid (ATRA) Mechanism (MCQ) ATRA binds to the PML-RAR fusion protein antagonizes Inhibitory effect of PML-RAR fusion protein on the transcription of target genes. Remarkably, the resulting activation of transcription overcomes the block in differentiation within 1 to 2 days the neoplastic promyelocytes begin to differentiate into neutrophils, which rapidly die. o Clinical Features. Most patients present within weeks or a few months due to pancytopenia Procoagulants and fibrinolytic factors released by AML with the t(15;17), exacerbate the bleeding tendency(MCQ) tumors with monocytic differentiation often infiltrate the skin (leukemia cutis) and the gingiva(MCQ) CNS spread is less common than in ALL. Myeloblastoma, Granulocytic sarcoma, or Chloroma. AML presents as a localized soft-tissue mass They inevitably progress to full-blown AML over time. o Prognosis. AML is a difficult disease to treat. AMLs with t(8;21) or inv(16) (MCQ) have a relatively good prognosis with conventional chemotherapy, particularly in the absence of c-KIT mutations prognosis is dismal for AMLs that (MCQ) follow MDS or genotoxic therapy occur in the elderly AML with poor prognosis is treated with bone marrow transplantation when possible.