Heterogeneity of clonal development in chronic myeloproliferative disorders

Abstract

Recent reports have suggested a previously unexpected variability in the expression of the dominant neoplastic clone in myeloproliferative disorders (MPD). We evaluated 49 female patients with MPD and informative at the X-linked androgen receptor (AR) locus to establish the X chromosome inactivation pattern of hemopoietic cells. Whereas in chronic myelogenous leukemia (CML) the granulocytes (PMN) were uniformly of monoclonal origin, a striking heterogeneity of clonal development was found in PMN from patients with other MPD, with up to 50% of them expressing a polyclonal pattern of X inactivation.

Telomere length dynamics in normal hematopoiesis and in disease states characterized by increased stem cell turnover

“…By taking advantage of random inactivation of X-chromosome-linked polymorphisms, clonality has been studied in CMPDs, initially by Fialkow and coworkers, [144][145][146][147] and later by other groups using different polymorphisms. [148][149][150] Interestingly, it seems as if clonality in CMPD is also linked to both shortened telomeres 151,152 as well as to significantly increased levels of telomerase activity 153 as opposed to nonclonal CMPD and normal bone marrow cells. Moreover, similar to what has been described in CML, 138 telomere length seems to be significantly reduced in (presumably clonal) myeloid cells as opposed to (non-clonal) T-lymphocytes.…”

Clonal granulocytes in polycythaemia vera and essential thrombocythaemia have shortened telomeres

“…Several studies however have shown that a sizeable proportion of patients with PV and ET have polyclonal granulopoiesis (Ferraris et al, 1999;Harrison et al, 1999;Liu et al, 2003). Our investigation was focused on PV and ET, and as we chose to exploit XCIP as marker of clonality, we found a significant correlation between monoclonal expression of XCIP and shorter telomere lengths in cells of myeloid origin; the seven clinically undistinguishable patients with polyclonal granulopoiesis were found to express a DTRF well within the control range (Fig 1).…”

“…Terasaki et al (2002) recently reported accelerated telomere shortening in 52AE5% of 35 patients with PV and ET. According to our experience, approximately 50% of patients with CMPDs other than CML may have polyclonal granulopoiesis (Ferraris et al, 1999(Ferraris et al, , 2005. Therefore, only PV and ET with clonal granulopoiesis have shortened telomeres and higher TA (Ferraris et al, 2005).…”

“…Without the aid of a specific cytogenetic marker, clonality studies have relied mainly on the analysis of X chromosome-linked polymorphic genes, whose expression is subject to random inactivation in females. Contrary to the general principle that PV and ET are monoclonal disorders, several studies have lately demonstrated through analysis of X chromosome inactivation pattern (XCIP) the heterogeneity of clonal development of myeloid cells in CMPDs other than chronic myelogenous leukaemia (CML) (Ferraris et al, 1999;Harrison et al, 1999;Liu et al, 2003).…”

High telomerase activity in granulocytes from clonal polycythemia vera and essential thrombocythemia

“…Several studies, however, have shown that a sizable proportion of patients with polycythemia vera (PV) and essential thrombocythemia (ET) have polyclonal hematopoiesis. [7][8][9] The significance of this variable clonal expression and its relationships, if any, with other clinical and/or biologic characteristics remain elusive.…”