Molecular Biology

The cause of markedly enhanced fibroblast proliferation and collagen synthesis in MF could relate to an array of humoral factors that may be released from hemopoietic cells, including both the megakaryocytes and monocytes. The fibroblasts themselves rarely display intrinsic alteration and are hence regarded as "effector cells." Megakaryocytes and platelets may influence fibroblast proliferation by virtue of their increased content, release, and abnormal packaging of alpha granule contents PDGF, PF-4, TGFp, b-FGF, and calmodulin.49 The subcellular location of P-selectin in megakaryocytes and platelets is abnormal and may correlate with emperipoiesis, which causes disruption of the megakaryocyte organelles and causes the leakage of a-granule contents.50 Monocytes have also been implicated in the stimulation of fibrosis. They are activated following contact with protein components of the extracellular matrix via adhesion molecules, particularly CD44, subsequently resulting in enhanced monocyte CD25 expression and increased production of TGFp and interleukin-1. The potential role for monocytes or macrophages or indeed other genetic factors in the pathogenesis of MF is supported by animal models. At a cellular level attention has focused upon growth factor pathway anomalies and the recent identification of V617F JAK2 and MPLW515L/K8'9 is in keeping with this. The aetiology of MF without JAK2 or cMPL mutations is unclear but the patients have all the features associated with MPD and while one publication51 suggests they may have superior prognosis this has not been identified in all studies.52

Probably the next major issue in MPDs is whether it is still relevant to subdivide V617F JAK2 positive or indeed negative disease into the three different entities (PV, ET, or MF) or is it preferable to regard the MPDs as a continuum of conditions akin to the different phases of CML. Here advanced MF or AML would represent advanced phase and ET with PV chronic phase. Unlike CML the rate of progression, if at all, of patients along this continuum is slow and patients may of course present at any point of the spectrum.

This proposal is contentious but is recently strengthened by several pieces of evidence from translational research. For example, Scott et al.32 found that none of the patients studied with ET had V617F JAK2 homozygous colonies, while such colonies were detected in all the PV patients (p < 0.0001) and two ET patients after polycthemic transformation. This suggests that a fundamental difference between ET and PV might be the mitotic recombination events that generate daughter cells homozygous for V617F JAK2. Evidence that total "load" of V617F JAK2 increases between the entities ET, PV, and MF (and post-polycythemic MF) has also been reported by other groups. For example Moliterno53 reports the median neutrophil JAK2 V617F allele percentage was greater in PV than in ET (p = <0.001), and that allele percentages greater than 63% were restricted to PV and MF. Similarly, Passamonti54 recently reported in 66/90 MPD patients that significant differences in quantity of V617F JAK2 occur between PV and ET (p = 0.01), or PV and prefibrotic MF (p = .005); fibrotic MF and pre-fibrotic MF (p = 0.001) and postpolycythemic MF having higher levels than PV (p < 0.001). This data accords with data from the group at the Mayo Clinic groups.55

These findings could be extrapolated to a model of the relationship between the V617F JAK2 positive MPDs and disease progression as shown in Figure 46.1. The challenges for this model are why the majority of ET patients do not transform to PV,which may relate to a genetic predisposition to undergo mitotic recombination, as well as to elucidate the additional genetic hits causing disease progression and why some patients progress more rapidly than others who do not progress at all.

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