Advances in Understanding the Biology and Genetics of Acute Myelocytic Leukemia

Shirlyn B McKenzie

doi:10.29074/ascls.18.1.28

This article has a correction. Please see:

“Advances in Understanding the Biology and Genetics of Acute Myelocytic Leukemia” and “Chronic Myelocytic Leukemia-Part I: History, Clinical Presentation, and Molecular Biology” - July 01, 2005

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Shirlyn B McKenzie, PhD CLS (NCA)⇑
1. is Professor and Chair of the Department of Clinical Laboratory Sciences at the University of Texas Health Science Center at San Antonio, San Antonio TX

Address for correspondence: Shirlyn B McKenzie PhD CLS(NCA), Department of Clinical Laboratory Sciences, UTHSCSA, 7703 Floyd Curl Dr, San Antonio TX 78229-3900. (210) 567-8860. mckenzie{at}uthscsa.edu

Explain the cancer stem cell hierarchical model and how it applies to acute myelocytic leukemias (AMLs).
Correlate cytogenetic and molecular genetic findings in the diagnosis and prognosis of AML.
Compare and contrast class I and class II mutations in AML and give examples of each.
Explain the functions of the PML/RARA fusion protein in promyelocytic leukemia (PML).
Propose what will occur at the molecular level when ATRA is given to patients with PML and correlate with clinical findings in the patients.
Assess how advances in our understanding of the biology and genetics of hematopoietic neoplasms has affected the classification of these disorders.
Compare and contrast hematologic remission, cytogenetic remission, and molecular remission.

Abstract

Acute myelocytic leukemia (AML) is a malignant neoplasm of hematopoietic cells characterized by an abnormal proliferation of myeloid precursor cells, decreased rate of self-destruction and an arrest in cellular differentiation. The leukemic cells have an abnormal survival advantage. Thus, the bone marrow and peripheral blood are characterized by leukocytosis with a predominance of immature cells, primarily blasts. As the immature cells accumulate in the bone marrow, they replace the normal myelocytic cells, megakaryocytes, and erythrocytic cells. This leads to a loss of normal bone marrow function and associated complications of bleeding, anemia, and infection. The incidence of AML increases with age, peaking in the sixth decade of life. In the United States, there are about 10,000 new cases of AML and 7,000 deaths in those with an AML diagnosis per year. Current molecular studies of AML demonstrate that it is a heterogeneous disorder of the myeloid cell lineage.

This paper will discuss the most recent understanding and research of the cellular origin of AML and associated common genetic mutations that fuel the neoplastic process. Also discussed are how these advances have impacted the classification, selection of therapy, and definition of complete remission in AML. Promyelocytic leukemia will be discussed in detail as this AML subtype reveals how our understanding of the biology and genetics of the disease has led to targeted therapy that results in a cure in up to 80% of patients.

ABBREVIATIONS: AML = acute myelocytic leukemia; APL = acute promyelocytic leukemia; ATRA = all trans retinoic acid; CBF = core binding factor; FAB = French-American-British; HDAC = histone deacetylase; ITD = internal tandem duplications; MDS = myelodysplastic syndrome; MLL = mixed lineage leukemia; NB = nuclear body; NCOR = nuclear corepressor; NK = natural killer; PML = promyelocytic leukemia; PTD = partial tandem duplications; RA = retinoic acid; RAR = retinoic acid receptor; TK = tyrosine kinase; WHO = World Health Organization.