Page 1468 - Williams Hematology ( PDFDrive )

1442 Part X: Malignant Myeloid Diseases Chapter 89: Chronic Myelogenous Leukemia and Related Disorders 1443

Variations in breakpoints involving smaller stretches of chromo- a syndrome mimicking human CML also occurred. Mice transgenic
some 9 and rearrangements outside the M-bcr of chromosome 22 can for a p190 BCR-ABL develop an acute lymphocytic leukemia (ALL) lym-
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occur. In a few cases of CML with no evident elongation of chromo- phoma syndrome that resembles human Ph chromosome–positive
some 9, molecular probes have shown that ABL1 still is translocated ALL. When a p210 BCR-ABL transcript is introduced into a mouse germ-
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to chromosome 22. In occasional patients with Ph chromosome– line (one-cell fertilized eggs), the p210 founder and progeny transgenic
positive CML, the break in chromosome 22 is outside the M-bcr, and animals developed leukemia of B or T lymphoid or of myeloid origin
transcription of a fusion RNA of the usual type fails or a fusion RNA after a relatively long latency period. In contrast, p190 transgenic mice
is transcribed that does not hybridize with the classic M-bcr comple- exclusively developed leukemia of B-cell origin, with a relatively short
mentary DNA (cDNA) probe. 174 period of latency. This finding was believed to be consistent with the
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In cases in which the Ph chromosome is not found, BCR-ABL1 still apparent indolent nature of human CML during the chronic phase.
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may be located on chromosome 9 (a masked Ph chromosome). The When transgenic mice express p210 BCR-ABL , the transgenes develop ALL,
BCR gene can recombine with genomically distinct sites on band 11q13 whereas the progeny develop a myeloproliferative disorder. 192
in complex translocations in a region rich in Alu repeat elements. Mouse models remain important for exploring the pathogenesis
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ETV6/ABL1 fusion genes have also been found in BCR-ABL1–negative of the acute and chronic BCR-ABL1–mediated leukemias in vivo and in
CML. 177 examining the potential effects of new drugs targeted at BCR-ABL1. 199
The BCR breakpoint site has been examined as a factor in disease
prognosis. Some studies have shown no correlation between CML chro-
nicity and breakpoint site, although thrombocytosis may be more com- BCR-ABL IN HEALTHY SUBJECTS
mon with 3′ breakpoint sites and basophilia with 5′ breakpoint sites. BCR-ABL1 fusion genes can be found in the leukocytes of some nor-
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No difference in response to IFN-α therapy was noted, and survival was mal individuals using a two-step reverse transcriptase polymerase chain
not significantly different, although patients with 3′ deletions tended to reaction assay. Thus, although BCR-ABL1 may be expressed relatively
have shorter survival. Others have observed a better response to IFN- frequently at very low levels in hematopoietic cells, only infrequently do
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α in patients with a 3′ rearrangement, which is being examined with the cells acquire the additional changes necessary to produce leukemia.
imatinib mesylate therapy. 180 This may be a dosage effect. 200
CML patients with m-bcr breakpoints develop a blast crisis with
monocytosis and an absence of splenomegaly and basophilia. The p230
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(e19a2 RNA junction) encoded by μ-bcr is rarely expressed but has been BCR-ABL1 AND SIGNAL TRANSDUCTION
associated with neutrophilic CML or thrombocytosis (see “Special Clin- The tyrosine phosphoprotein kinase activity of p210 BCR-ABL1 has been
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ical Features” below). Other rare breakpoints have been described. For causally linked to the development of Ph chromosome–positive leuke-
example, a case with a 12-bp insert between BCR and ABL1 resulted in mia in man. 201–212 p210 BCR-ABL1 is, unlike the ABL1 protein that is located
a BCR-ABL1–negative (false-negative), Ph chromosome–positive CML principally in the nucleus, located in the cytoplasm making it accessible
with thrombocythemia. Another novel BCR-ABL1 fusion gene (e6a2) to a large number of interactions, especially components of signal trans-
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in a patient with Ph chromosome–negative CML encoded an oncopro- duction pathways. 205,206,213 It binds and/or phosphorylates more than
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tein of 185 kDa. Typical CML also has been associated with an e19a2 20 cellular proteins in its role as an oncoprotein. A subunit of phos-
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junction BCR-ABL1 transcript. 185 phatidylinositol 3′-kinase (PI3K) associates with p210 BCR-ABL ; this inter-
Experimental support for the hypothesis that p210 BCR-ABL1 tyrosine action is required for the proliferation of BCR-ABL1–dependent cell
phosphoprotein kinase is transforming is provided by a retroviral gene lines and primary CML cells. Wortmannin, a nonspecific inhibitor of
transfer system that permits expression of the protein. Mouse marrow the p110 subunit of the kinase, inhibits growth of these cells. 207
cells transfected with BCR-ABL1 develop clonal outgrowths of immature The pathways and interactions invoked by BCR-ABL1 acting
cells expressing the p210 BCR-ABL1 tyrosine kinase. Some clones progress to on mitogen-activated protein kinases are multiple and complex. 214,215
a malignant phenotype, can be transplanted, and can induce tumors in A RAF-encoded serine-threonine kinase activity is regulated by
syngeneic mice. Similar studies suggest that the p210 BCR-ABL can trans- p210 BCR-ABL . Downregulation of RAF expression inhibits both BCR-
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form 3T3 murine fibroblasts if the gag gene sequence from a helper ABL1–dependent growth of CML cells and growth factor–dependent
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virus cooperates. The BCR-ABL1 gene from a retroviral vector has proliferation of normal hematopoietic progenitors. The efficiency of
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been expressed in an IL-3–dependent cell line. Clones derived from the cell transformation by BCR-ABL1 is affected by an adaptor protein that
infected line transform over months to IL-3 independency, are capable can relate tyrosine kinase signals to RAS. This involves growth factor
of increased proliferation, and develop chromosomal abnormalities. 188 receptor–bound protein-2 (GRB2). p210 BCR-ABL also activates multiple
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A series of mouse models in which the BCR-ABL1 was used to alternative pathways of RAS. PI3K is constitutively activated by BCR-
induce leukemogenesis have been described. 189–197 Lethally irradiated ABL1, generates inositol lipids, and is dysregulated through the down-
mice have been reconstituted with marrow enriched for cycling stem regulation by BCR-ABL1 of polyinositol phosphate tumor suppressors,
cells infected with a BCR-ABL1–bearing retrovirus. Fatal diseases such as PTEN and SHIP1. Figure 89–5 demonstrates interaction of
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with abnormal accumulations of macrophagic, erythroid, mast, and p210 BCR-ABL with various mediators of signal transduction.
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lymphoid cells develop. Classic CML did not occur, and complete Reactive oxygen species are increased in BCR-ABL1–transformed
transformation was not documented. The cell lines from spleen and cells and may act as a second messenger to modulate enzymes regulated
marrow from mice with a BCR-ABL1 retrovirus infection were pre- by the reduction-oxidation (redox) equilibrium. An increase in these
dominantly mast cells; however, in some cases these cell lines sponta- reactive oxygen products is postulated to play a role in the acquisition of
neously switched to either erythroid and megakaryocytic, erythroid, or additional mutations as a result of production of reactive oxygen species
granulocytic lineages displaying maturation. They were transplantable through the chronic phase, contributing to the progression to acceler-
(transformed) and contained the same proviral inserts as the original ated phase. 213,216
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mast cell line. Murine marrow also has been infected with a retrovirus The adaptor molecule CRKL is a major in vivo substrate for
encoding p210 BCR-ABL and transplanted into irradiated syngeneic recipi- p210 BCR-ABL , and it acts to relate p210 BCR-ABL to downstream effectors.
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ents. Although several types of hematologic malignancies developed, CRKL is a linker protein that has homology to the v-crk oncogene

Kaushansky_chapter 89_p1437-1490.indd 1443 9/18/15 3:41 PM