Genetic Abnormalities and Challenges in the Treatment of Acute Myeloid Leukemia

Onconova Therapeutics Inc., Pennington, NJ, USA.
Genes & cancer 02/2011; 2(2):95-107. DOI: 10.1177/1947601911408076
Source: PubMed


Acute myeloid leukemia (AML) is a hematopoietic disorder in which there are too many immature blood-forming cells accumulating in the bone marrow and interfering with the production of normal blood cells. It has long been recognized that AML is a clinically heterogeneous disease characterized by a multitude of chromosomal abnormalities and gene mutations, which translate to marked differences in responses and survival following chemotherapy. The cytogenetic and molecular genetic aberrations associated with AML are not mutually exclusive and often coexist in the leukemic cells. AML is a disease of the elderly, with a mean age of diagnosis of 70 years. Adverse cytogenetic abnormalities increase with age, and within each cytogenetic group, prognosis with standard treatment worsens with age. In the past 20 years, there has been little improvement in chemotherapeutic regimens and hence the overall survival for patients with AML. A huge unmet need exists for efficacious targeted therapies for elderly patients that are less toxic than available chemotherapy regimens. The multitude of chromosomal and genetic abnormalities makes the treatment of AML a challenging prospect. A detailed understanding of the molecular changes associated with the chromosomal and genetic abnormalities in AML is likely to provide a rationale for therapy design and biomarker development. This review summarizes the variety of cytogenetic and genetic changes observed in AML and gives an overview of the clinical status of new drugs in development.

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    • "Acute leukemia constitutes a group of oncohematologic diseases with a multifactorial origin [1, 2]; acute lymphoid leukemia (ALL) and acute myeloid leukemia (AML) are characterized by the excessive proliferation of immature hematopoietic cells (blasts) in the bone marrow. Progressive accumulation of these cells in the peripheral blood leads to the development of fatal infections, hemorrhages, and in many cases to death [3–5]. "
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    ABSTRACT: Among oncohematological diseases, acute lymphoid leukemia (ALL) and acute myeloid leukemia (AML) are characterized by the uncontrolled production and accumulation of blasts that can lead to death. Although the physiopathology of these diseases is multifactorial, a genetic factor seems to be at play. Several studies worldwide have shown association of ALL and AML with several alleles of the major histocompatibility complex (MHC). Objective. To determine gene frequencies of HLA-B alleles in Mexicans (individuals with Native American genetic background admixed with European descent) with ALL and AML. Methods. We compared the HLA-B alleles in 213 patients with ALL and 85 patients with AML to those present in 731 umbilical cord blood (UCB) samples as a control group; this was done by means of the PCR-SSP technique. Results. We found an increased frequency of the HLA-B*40 allele in ALL patients as compared to the control group (14.5% versus 9.84%, P = 0.003, OR = 1.67); this was particularly evident in a subgroup of young (less than 18 years old) ALL patients (P = 0.002, OR = 1.76); likewise, a decreased frequency of HLA-B*40 allele in AML patients was observed as compared to the control group (4.70% versus 9.84%, P = 0.02, OR = 0.42). Conclusions. These results might suggest opposing effects of the HLA-B*40 in the genetic susceptibility to develop ALL or AML and offer the possibility to study further the molecular mechanisms of cell differentiation within the bone marrow lineage.
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    ABSTRACT: RESUMEN La leucemia mieloblástica aguda se caracteriza por la extrema proliferación clonal de precursores hematopoyéticos indiferenciados o con diferenciación anormal. La quimioterapia está dirigida a la reducción y erradicación de células leucémicas. Sin embargo, generalmente se asume que la recaída ocurre gracias a la coexistencia de células residuales, que son resistentes o eluden la terapia. Durante los últimos años, la hipótesis de la célula madre cancerosa ha ganado considerable importancia y podría interpretar este comportamiento. Esta teoría persuasiva establece que dentro de un tumor, las células están organizadas en una jerarquía similar a la encontrada en los como "células iniciadoras de tumor" poseen varias propiedades de células madre de tejidos normales. Hace poco se demostró que las "células iniciadoras de tumor" asociadas con la leucemia mieloblástica aguda forman una clase distinta en una jerarquía similar a la observada en las células madre hematopoyéticas. Ahora sabemos que en la leucemia mieloblástica aguda el crecimiento y supervivencia de los blastos se lleva acabo por los mismos factores de crecimiento que estimulan a las células normales. Más aun, se ha puesto en evidencia el papel que juega el factor de crecimiento de la célula madre de tipo membranal y su receptor c-Kit en las interacciones célula-señales de c-Kit induce combinaciones de muerte celular: autofagia (mecanismo compensatorio hacia la supervivencia) y apoptosis. Los inhibidores de c-Kit no sólo reducen la proliferación de células cancerosas sino que también pueden, usados inapropiadamente, deteriorar tejidos normales. El propósito de este artículo es revisar algunas de las características importantes de los blastos leucémicos en vista de la investigación realizada. En lugar de presentar detalles de varios estudios se intentan indicar áreas generales de trabajo realizado o en evolución. Se espera que este ensayo muestre otras oportunidades de investigación en la leucemia mieloblástica aguda. Palabras clave: leucemia mieloblástica aguda, células madre cancerosas, autofagia, apoptosis. ABSTRACT Acute myeloblastic leukaemia is characterized by the extreme clonal proliferation of haematopoietic precursor cells with abnormal or arrested differentiation. Chemotherapy of acute leukaemia is channelled towards the reduction and eradication of leukaemic cells. However, relapse is generally assumed to occur in residual host cells, which are refractory to or elude therapy. The cancer stem cell hypothesis has gained considerable importance in recent years and could interpret this behaviour. This persuasive theory states that cells within a tumour are organized in a hierarchy similar to that of normal tissues, and are maintained by a small subset of cells responsible for tumour associated with AML have been shown to comprise distinct, hierarchically arranged classes similar to those observed for haematopoietic stem cells. We know now that the growth and survival of blasts in AML are driven by the same growth factors that stimulate normal cells. Furthermore, direct evidence of the role of membrane steel factor and its receptor c-Kit in cell-cell interactions and cell survival in primary cell proliferation, it also demonstrated that future inappropriate prescriptions could cause normal tissue deterioration. The purpose of this paper was to review some of the salient features of leukaemic blasts in support of the proposal that research into neoplasia be increased. Rather than presenting the details of various studies, I have attempted to indicate general areas in which work has been done or is in progress. It is hoped that this survey of the subject will demonstrate a variety of opportunities for additional research in human neoplasia.
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