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Hematogones: Fiction Or Reality

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Hematogones: Fiction Or Reality HEMATOGONES: FICTION OR REALITY Alberto Orfao Department of Medicine, Cancer Research Centre (IBMCC-CSIC/USAL), University of Salamanca, Salamanca, Spain The term hematogones has been long used acquisition of the most specific pan-B cell marker: to describe benign lymphoid precursors which CD19 at the stage of a pre-pre-B cell (pre-B I cell). typically appear at increased numbers in the bone When maturing these cells decrease their light marrow of children after they received chemother- scatter properties -low forward (FSC) and sideward apy, although they can be also observed in other light scatter (SSC)- and show high expression of reactive conditions. From both a morphological both CD10 and CD38 (pre-pre-B cell). Then, these and immunophenotypical point of view hemato- early pre-B cell precursors progressively increase gones are rather similar to acute lymphoblastic expression of CD45, they become CD20+ and leukemia (ALL) blast cells. Because of their great down-regulate (from strong to dim) CD10 expres- morphological, and also immunophenotypic simi- sion leading to a CyIgm+ pre-B cell (pre-B II cell). larities with ALL blasts, hematogones may cause As soon as the pre-B cell becomes CD10low/ diagnostic problems. From the biological point CD20+, expression of SmIgM with either SmIgk of view, the expansion of hematogones typically or SmIgl light chains becomes detectable to reach reflects an increased production of B-cells which very high levels in the transition from a pre-B cell more commonly occurs in children bone marrow, to an immature B-lymphocyte. Immature (also several months (e.g. 2 to 5) after initiation of che- termed transitional) B-lymphocytes undergo up- motherapy. Although the precise clinical signifi- regulation of CD5 and CD23, and down regula- cance of expanded hematogones still remains to be tion of both CD10 and CD38 as soon as they fully understood, biologic characterization of these undergo maturation to a mature naïve smIgM+, cells still remains incomplete. Despite this, current SmIgD+ B-lymphocyte; both immature and naïve knowledge about the unique immunophenotypic B-lymphocytes can already be detected in steady- and molecular features of hematogones versus state peripheral blood, while more immature B-cell blast cells allows their discrimination in human precursors are normally undetectable in peripheral bone marrow. blood and can only be seen in stressed conditions (e.g. after chemotherapy or Rituximab ttreatment). From the phenotypic point of view, hemato- gones usually correspond to B-cell precursors Such detailed knowledge about the immu- at relatively early stages of maturation. Commit- nophenotypic sequence of expression of mul- ment of hematopoietic precursors into the B-cell tiple B-cell precursor associated proteins, facili- lineage is first identified by coexpression on a tates the identification of the presence of aber- CD34+ hematopoietic precursor of the terminal rant phenotypes involving B-cell precursor ALL deoxynucleotidyl transferase (Tdt) enzyme involved blasts. Accordingly, blasts and hematogones can in immunoglobulin (Ig) gene rearrangements and be currently distinguished because of the aber- the CD79a B-cell receptor molecule, in the cell rant expression of markers typical of other (e.g. nuclei (n) and cytoplasm (Cy), respectively. Almost T or myeloid) cell lineages –cross-lineage antigen in parallel this early B-cell precursor (pro-B cell) expression-, over- or underexpression of individual also shows expression of CD22, CD10 and CD81 cell surface proteins, and asynchronous expression on the cell surface membrane (Sm), just prior to of maturation-associated proteins –asynchronous 68 XXXVII. Ulusal Hematoloji Kongresi antigen expression-. Examples of such aberrant multiparametric flow cytometry approaches, it can phenotypes include: i) coexpression of CD13, also be clearly demonstrated that regenerating CD33, CD66 and/or CD15 and CD65, ii) overex- hematogones are immunophenotypically similar to pression of CD10 and CD58 and underexpression normal B-cell precursors at early stages of matura- of CD45 and/or Cy/SmIg, and, iii) asynchronous tion, although they are increased in regenerating expression of CD38low, CD20high on CD34+, childhood bone marrow samples typically between CD19+ cells. In recent years, such aberrant phe- one and five months after induction chemotherapy. notypes have been shown to allow the detection This will have relevant implications in the manage- of aberrant phenotypes and distinction between ment of ALL patients, through improved and more normal and leukemic B-cell precursors in virtually efficient flow cytometry-based assessment of mini- every all patients with B-cell precursor ALL (BCP- mal residual disease (MRD) levels in childhood and ALL), studied at diagnosis. Despite this, usage of adult bone marrow, after therapy. conventional approaches based on 4-color stain- ings, is frequently associated with a limited sen- In summary, it can be concluded that despite sitivity of detection of blast cells when assessed in the great similarities between hematogones and bone marrow samples which contain high numbers leukemic ALL blasts, current multicolour, multipa- of hematogones. Usage of >8-color stainings in rametric flow cytometry data analysis approaches, combination with new multivariate data analysis provide a reliable and reproducible tool for effi- approaches appears to overcome such limited sen- cient discrimination between both types of cells in sitivity and limitations. Based on these multicolour, human (childhood and adult) bone marrow. 19-22 Ekim 2011, Ankara 69.
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