New markers for minimal residual disease detection in acute lymphoblastic leukemia

Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA.
Blood (Impact Factor: 10.45). 06/2011; 117(23):6267-76. DOI: 10.1182/blood-2010-12-324004
Source: PubMed

ABSTRACT To identify new markers for minimal residual disease (MRD) detection in acute lymphoblastic leukemia (ALL), we compared genome-wide gene expression of lymphoblasts from 270 patients with newly diagnosed childhood ALL to that of normal CD19⁺CD10⁺ B-cell progenitors (n = 4). Expression of 30 genes differentially expressed by ≥ 3-fold in at least 25% of cases of ALL (or 40% of ALL subtypes) was tested by flow cytometry in 200 B-lineage ALL and 61 nonleukemic BM samples, including samples containing hematogones. Of the 30 markers, 22 (CD44, BCL2, HSPB1, CD73, CD24, CD123, CD72, CD86, CD200, CD79b, CD164, CD304, CD97, CD102, CD99, CD300a, CD130, PBX1, CTNNA1, ITGB7, CD69, CD49f) were differentially expressed in up to 81.4% of ALL cases; expression of some markers was associated with the presence of genetic abnormalities. Results of MRD detection by flow cytometry with these markers correlated well with those of molecular testing (52 follow-up samples from 18 patients); sequential studies during treatment and diagnosis-relapse comparisons documented their stability. When incorporated in 6-marker combinations, the new markers afforded the detection of 1 leukemic cell among 10(5) BM cells. These new markers should allow MRD studies in all B-lineage ALL patients, and substantially improve their sensitivity.

34 Reads
  • Source
    • "B. IRF4-associated gene expression pattern in leukemia. The dataset includes 288 B- and T-cell acute lymphoblastic leukemia samples [45]. 0. CD10+;CD19+ hematogone (4 samples); 1. B-Cell childhood acute lymphoblastic leukemia (238 samples); 2. T-cell childhood acute lymphoblastic leukemia (46 samples). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The lymphocyte-specific transcription factor Interferon (IFN) Regulatory Factor 4 (IRF4) is implicated in certain types of lymphoid and myeloid malignancies. However, the molecular mechanisms underlying its interactions with these malignancies are largely unknown. In this study, we have first profiled molecular signatures associated with IRF4 expression in associated cancers, by analyzing existing gene expression profiling datasets. Our results show that IRF4 is overexpressed in melanoma, in addition to previously reported contexts including leukemia, myeloma, and lymphoma, and that IRF4 is associated with a unique gene expression pattern in each context. A pool of important genes involved in B-cell development, oncogenesis, cell cycle regulation, and cell death including BATF, LIMD1, CFLAR, PIM2, and CCND2 are common signatures associated with IRF4 in non-Hodgkin B cell lymphomas. We confirmed the correlation of IRF4 with LIMD1 and CFLAR in a panel of cell lines derived from lymphomas. Moreover, we profiled the IRF4 transcriptome in the context of EBV latent infection, and confirmed several genes including IFI27, IFI44, GBP1, and ARHGAP18, as well as CFLAR as novel targets for IRF4. These results provide valuable information for understanding the IRF4 regulatory network, and improve our knowledge of the unique roles of IRF4 in different hematological malignancies.
    PLoS ONE 09/2014; 9(9):e106788. DOI:10.1371/journal.pone.0106788 · 3.23 Impact Factor
  • Source
    • "In a more recent study Coustan-Smith and coworkers carried out an analysis on 270 patients with newly diagnosed childhood ALL based on the analysis by flow cytometry of 30 membrane antigens, including CD123 [38]. Of these 30 markers, 22 were differentially expressed in ALL cases compared to CD19+CD10+ B-cell progenitors; particularly, CD123 was markedly more expressed in the majority of cases on B-ALL blasts, compared to normal B cell progenitors [38]. Some of these markers, including CD123 were shown to be very useful fo the detection of minimal residual disease, even at the level of the definition of a very minor residual lymphoid leukemic cell population [38]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent studies indicate that abnormalities of the alpha-chain of the interleukin-3 receptor (IL-3RA or CD123) are frequently observed in some leukemic disorders and may contribute to the proliferative advantage of leukemic cells. This review analyzes the studies indicating that CD123 is overexpressed in various hematologic malignancies, including a part of acute myeloid and B-lymphoid leukemias, blastic plasmocytoid dendritic neoplasms (BPDCN) and hairy cell leukemia. Given the low/absent CD123 expression on normal hematopoietic stem cells, attempts have been made at preclinical first, and then at clinical level to target this receptor. Since the IL-3R is a membrane receptor there are two relatively simple means to target this molecule, either using its natural ligand or neutralizing monoclonal antibodies. Recent reports using a fusion molecule composed by human IL-3 coupled to a truncated diphteria toxin have shown promising antitumor activity in BPDCN and AML patients.
    02/2014; 2(1):4. DOI:10.1186/2050-7771-2-4
  • Source
    • "Methods to study MRD by flow cytometry are constantly being refined by the introduction of new markers [80], which take advantage of the capacity of newer instruments to detect an increasingly higher number of fluorochromes. Technologies relying on mass spectrometry-based detection of elements conjugated to antibodies can further increase this capability [81]; their utility for MRD detection is yet untested. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Measuring response to chemotherapy is a backbone of the clinical management of patients with acute leukemia. This task has historically relied on the ability to identify leukemic cells among normal bone marrow cells by their morphology. However, more accurate ways to identify leukemic cells have been developed, which allow their detection even when they are present in small numbers that would be impossible to be recognized by microscopic inspection. The levels of such minimal residual disease (MRD) are now widely used as parameters for risk assignment in acute lymphoblastic leukemia (ALL) and increasingly so in acute myeloid leukemia (AML). However, different MRD monitoring methods may produce discrepant results. Moreover, results of morphologic examination may be in stark contradiction to MRD measurements, thus creating confusion and complicating treatment decisions. This review focusses on the relation between results of different approaches to measure response to treatment and define relapse in childhood acute leukemia.
    The Korean journal of hematology 12/2012; 47(4):245-54. DOI:10.5045/kjh.2012.47.4.245
Show more