Cytogenetic and genetic pathways in therapy-related acute myeloid leukemia

doi:10.1016/j.cbi.2009.11.025

Chemico-Biological Interactions

Volume 184, Issues 1–2, 19 March 2010, Pages 50-57

https://doi.org/10.1016/j.cbi.2009.11.025 Get rights and content

Abstract

Therapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/t-AML) are late complications of cytotoxic therapy used in the treatment of malignant diseases. The most common subtype of t-AML (∼75% of cases) develops after exposure to alkylating agents, and is characterized by loss or deletion of chromosome 5 and/or 7 [−5/del(5q), −7/del(7q)], and a poor outcome (median survival 8 months). In the University of Chicago's series of 386 patients with t-MDS/t-AML, 79 (20%) patients had abnormalities of chromosome 5, 95 (25%) patients had abnormalities of chromosome 7, and 85 (22%) patients had abnormalities of both chromosomes 5 and 7. t-MDS/t-AML with a −5/del(5q) is associated with a complex karyotype, characterized by trisomy 8, as well as loss of 12p, 13q, 16q22, 17p (TP53 locus), chromosome 18, and 20q. In addition, this subtype of t-AML is characterized by a unique expression profile (higher expression of genes) involved in cell cycle control (CCNA2, CCNE2, CDC2), checkpoints (BUB1), or growth (MYC), loss of expression of IRF8, and overexpression of FHL2. Haploinsufficiency of the RPS14, EGR1, APC, NPM1, and CTNNA1 genes on 5q has been implicated in the pathogenesis of MDS/AML. In previous studies, we determined that Egr1 acts by haploinsufficiency and cooperates with mutations induced by alkylating agents to induce myeloid leukemias in the mouse. To identify mutations that cooperate with Egr1 haploinsufficiency, we used retroviral insertional mutagenesis. To date, we have identified two common integration sites involving genes encoding transcription factors that play a critical role in hematopoiesis (Evi1 and Gfi1b loci). Of note is that the EVI1 transcription factor gene is deregulated in human AMLs, particularly those with −7, and abnormalities of 3q. Identifying the genetic pathways leading to t-AML will provide new insights into the underlying biology of this disease, and may facilitate the identification of new therapeutic targets.

Introduction

t-MDS and t-AML are late complications of cytotoxic therapy (radiation and/or chemotherapy) used in the treatment of both malignant and non-malignant diseases [1], [2], [3], [4]. Several distinct cytogenetic and clinical subtypes of t-MDS/t-AML are recognized that are closely associated with the nature of the preceding treatment. Rowley et al. first noted the association of loss or deletion of chromosomes 5 and/or 7 with t-MDS/t-AML [5]. Subsequently, it was recognized that abnormalities of chromosomes 5 and/or 7 are the hallmark of t-MDS/t-AML following alkylating agent therapy [4], [6], [7]. Patients who develop t-MDS/t-AML in this setting typically show a latency of 3–7 years from alkylating agent exposure (median 5 years), insidious disease onset with an antecedent MDS with peripheral cytopenias, and a poor prognosis (median survival <8 months) [1]. Typically, all three hematopoietic cell lineages (erythroid, myeloid, and megakaryocytic) are involved in the dysplastic process (trilineage dysplasia), suggesting that the disease arises in a multipotent hematopoietic stem (HSC) or progenitor cell (HPC).

In contrast, patients who develop t-AML following treatment with drugs targeting topoisomerase II are younger, have a shorter latency period (2–3 years), and rarely present with MDS. Overall, these patients have a more favorable response to intensive remission induction therapy than do t-AML patients with abnormalities of chromosomes 5 and/or 7 [4], [8]. Balanced translocations involving MLL at 11q23, RUNX1 at 21q22, CBFB at 16q22, or PML (15q22) and RARA (17q12) are common in this subgroup, suggesting that these cytogenetic subsets of t-AML arise in a lineage committed progenitor cell. t-MDS/t-AML arising after alkylating agent therapy represents the largest subgroup of patients (80–85%), whereas t-AML with balanced translocations represents ∼15% of cases [4]. Survival times of t-AML patients are often short, because this disorder is less responsive to current forms of therapy than is AML de novo[1], [3], [4].

t-AML represents an important model for cancer. The incidence of t-AML is rising, as a result of the increasing number of cancer survivors at risk of developing this disorder and the changes in therapeutic trends. t-AML also provides a unique opportunity to examine the effects of mutagens on carcinogenesis in humans, as well as the role of genetic susceptibility to cancer [3]. In this regard, Knight et al. used a low-resolution genome-wide association study, and identified novel loci associated with susceptibility to t-AML, providing proof-of-principle for this methodological approach [9]. Finally, the mechanisms of leukemogenesis that are uncovered in t-AML will likely apply to those subtypes of AML de novo which share the same cytogenetic abnormalities, e.g., AML de novo with abnormalities of chromosome 5 or 7. In this study, we review the genetic characteristics of t-MDS/t-AML with an emphasis on defining the genetic pathways leading to t-AML with a del(5q).

Section snippets

Cytogenetic analyses

Table 1 summarizes the cytogenetic pattern in the recently updated University of Chicago series of 386 consecutive patients with t-MDS/t-AML. Of these, 349 (90.4%) had a clonal chromosomal abnormality, including 259 (67%) with a clonal abnormality leading to loss or deletion of chromosomes 5 and/or 7 ([4], Le Beau and Larson, unpublished data). Overall, 164 patients (42%) had abnormalities of chromosome 5, and 180 (47%) had abnormalities of chromosome 7. Eighty-five patients had abnormalities

Alterations in gene function

A growing body of evidence suggests that mutations of multiple genes are involved in the pathogenesis and progression of t-MDS/t-AML. The involved genes fall into two main classes, namely, genes encoding hematopoietic transcription factors, or proteins that regulate cytokine signaling pathways (Table 2). The RAS signaling cascade is downstream of a number of activated cytokine receptors, including the FLT3, IL3, and GM-CSF receptors; thus, this signaling pathway plays a pivotal role in

Gene expression profiling of CD34+ progenitor cells in t-AML patients

To expand our understanding of the molecular basis of t-AML, we performed expression profiling of CD34+ progenitor cells from bone marrow samples from 14 t-AML patients using the Affymetrix platform [18]. Although many of the leukemias contained multiple cytogenetic abnormalities, we identified two major groups (A and B) with unique expression profiles. Group A included all patients with −7, but no abnormality of chromosome 5. In contrast, patients with an abnormality of chromosome 5 (with or

Molecular models for abnormalities of chromosomes 5 and 7 in myeloid disorders

The genetic consequences of a deletion may be a reduction in the level of one or more critical gene products (haploinsufficiency), or complete loss of function. The latter model, known as the “two-hit model”, predicts that loss of function of both alleles of the target gene would occur, in one instance through a detectable chromosomal loss or deletion and, in the other, as a result of a subtle inactivating mutation, or other mechanisms, such as transcriptional silencing. The relatively long

Cytogenetic and molecular delineation of the commonly deleted segment of 5q

Several groups of investigators have defined a CDS on the long arm of chromosome 5 predicted to contain a myeloid TSG (Fig. 2) [24], [25], [26]. To determine the location of genes on 5q that may be involved in leukemogenesis, we previously examined the deletions in 177 patients, including 44 patients who had t-MDS/t-AML, 116 patients who had MDS or AML de novo, and 17 patients who had the 5q− syndrome [20], [24]. This analysis revealed that these deletions were interstitial, and allowed us to

Identification of haploinsufficient myeloid suppressor genes on 5q

Despite intense efforts, the identification of TSGs on chromosomes 5 and 7 has been challenging. Molecular analysis of the 20 candidate genes within the CDS of 5q31.2 performed in our laboratory did not reveal inactivating mutations in the remaining alleles, nor was there evidence of transcriptional silencing ([20], and Godley and Le Beau, unpublished data). Similarly, molecular analysis of all 44 genes mapping to the CDS in 5q33.1 in the 5q− syndrome did not reveal inactivating mutations [26].

Models for the pathogenesis of t-AML

Extensive experimental evidence indicates that more than one mutation is required for the pathogenesis of hematological malignant diseases. Moreover, these mutations cooperate to confer a proliferative and/or antiapoptotic activity, as well as impair normal differentiation pathways. Haploinsufficiency for a gene(s) on 7q and 5q is likely to be an initiating mutation. Pedersen-Bjergaard et al. have proposed eight different pathways that are involved in progression to t-AML [38]. Pathway I

Concluding remarks

t-MDS/t-AML remains one of the most adverse complications of successful therapy for a variety of malignant and non-malignant conditions. The factors that place individual patients at risk are beginning to be elucidated, and are critical for risk-assessment, and to allow individualized therapy directed at minimizing the development of this disease. Moreover, characterizing the genetic pathways that give rise to t-MDS/t-AML will lead to a greater understanding of the molecular features of the

Conflict of interest statement

None

Acknowledgements

We thank the patients, and the many members of the Leukemia Program at the University of Chicago who participated in these studies, especially Drs. Sonali M. Smith, Theodore Karrison, and Lucy A. Godley.

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^☆: Supported by grants CA40046 and CA14599 from the National Cancer Institute.

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Cytogenetic and genetic pathways in therapy-related acute myeloid leukemia☆

Abstract

Introduction

Section snippets

Cytogenetic analyses

Alterations in gene function

Gene expression profiling of CD34+ progenitor cells in t-AML patients

Molecular models for abnormalities of chromosomes 5 and 7 in myeloid disorders

Cytogenetic and molecular delineation of the commonly deleted segment of 5q

Identification of haploinsufficient myeloid suppressor genes on 5q

Models for the pathogenesis of t-AML

Concluding remarks

Conflict of interest statement

Acknowledgements

Semin. Oncol.

Blood

Blood

Blood

Blood

Blood

Genomics

Biochim. Biophys. Acta

Blood

Blood

Blood

Cell

Cell Stem Cell

Cell

Blood

Mechanisms of therapy-related carcinogenesis

Nat. Rev. Cancer

Cytogenetic characteristics of therapy-related acute nonlymphocytic leukaemia, preleukaemia and acute myeloproliferative syndrome: correlation with clinical data for 61 consecutive cases

Br. J. Haematol.

Chromosome analysis of 63 cases of secondary nonlymphoid blood disorders: a cooperative study, Groupe Francais de Cytogenetique Hematologique

Cancer Genet. Cytogenet.

Balanced translocations involving chromosome bands 11q23 and 21q22 are highly characteristic of myelodysplasia and leukemia following therapy with cytostatic agents targeting at DNA-topoisomerase II

Blood