Page 203 - Williams Hematology ( PDFDrive )

178 Part IV: Molecular and Cellular Hematology Chapter 13: Cytogenetics and Genetic Abnormalities 179

Several types of genetic changes are associated with imatinib resis- Cytogenetic analysis of cells from patients with primary myel-
tance, including point mutations leading to amino acid substitutions in ofibrosis has revealed clonal abnormalities in 60 percent of patients
the BCR-ABL1 kinase domain that interfere with imatinib binding, as (Chap. 86). These abnormalities are similar to those noted in other
19
well as the acquisition of additional copies of the Ph chromosome or myeloid disorders. The most common anomalies are +8, −7, or a
BCR-ABL1 gene amplification, both of which can be detected by FISH. del(7q), del(11q), del(13q), and del(20q). A change in the karyotype
19
14
Besides duplications of the BCR-ABL1 fusion, additional TKI resis- may signal evolution to AML. Fewer than 10 percent of patients with
tance-associated genomic lesions, including acquired regions of LOH essential thrombocythemia have an abnormal clone (Chap. 85). Recur-
on chromosomes 1, 8, 9, 17, 19, and 22, have been detected by SNP ring abnormalities include +8 and del(13q). Although del(5q) and
array analysis. Although some patients who achieve a complete cyto- inv(3)/t(3;3) are associated with thrombocytosis, they are characteristic
15
genetic response on imatinib develop clonal karyotypic abnormalities, of MDS or AML, rather than essential thrombocythemia.
most commonly +8, −7, or del(20q), the majority of them do not go on Mutant JAK2 V617F is a constitutively active tyrosine kinase that acti-
to develop the clinical features of MDS. The significance of these early vates the STAT, PI3Ks, and mitogen-activated protein kinases (MAPKs)
16
findings will be elucidated by the analysis of a large number of patients signalling pathways downstream of the erythropoietin receptor, throm-
who have had complete cytogenetic responses to TKIs and are being bopoietin receptor, or the granulocyte colony-stimulating factor (G-CSF)
followed prospectively. receptor to promote proliferation and transformation of hematopoietic
As they enter the more aggressive stages of accelerated and blast progenitor cells (Chap. 84). JAK2 mutations occur in polycythemia vera
phase disease, historically 80 percent of CML patients showed karyo- (95 percent), essential thrombocythemia (approximately 50 percent),
typic evolution with the appearance of new chromosomal abnormalities and myelofibrosis (approximately 50 percent) (Chaps. 84 to 86). In
20
in very distinct patterns in addition to the Ph chromosome. A change in refractory anemia with ring sideroblasts (RARS) with thrombocytosis
the karyotype was considered to be a grave prognostic sign. The most (RARS-t), a MDS/MPN, unclassified by the World Health Organiza-
17
common changes, a gain of chromosomes 8 or 19, or a second Ph chro- tion (WHO) classification, 60 percent of patients have the JAK2 V617F
mosome (by gain of the first), or an i(17q), frequently occurred in com- mutation, and present with higher white blood cell and platelet counts
bination to produce modal chromosome numbers of 47 to 50. Other (Chap. 87). Less commonly, activation of the JAK-STAT pathway in
21
genetic changes identified in CML in blast crisis include mutations in MPNs may result from JAK2 exon 12 mutations (1 to 2 percent of poly-
the TP53, RB1, MYC, CDKN2A (p16), KRAS/NRAS, or RUNX1/AML1 cythemia vera cases) or mutation of the thrombopoietin receptor, MPL
genes. With the advent of TKI therapy, the natural history of CML has (approximately 2 percent of essential thrombocythemia and approx-
been altered, and the karyotype in blast phase appears to differ from imately 5 percent of myelofibrosis). The majority of essential throm-
that seen previously. However, the pattern of abnormalities is not yet bocythemia and myelofibrosis patients with nonmutated JAK2 carry
well described. somatic mutations in the calreticulin gene (CALR) (Chaps. 85 and 86). 22,23
Rarely, marrow biopsies from patients will appear similar to those
patients with CML, but will lack a Ph chromosome or the BCR-ABL1 MYELODYSPLASTIC SYNDROMES
fusion. Most often these patients have a MDS or myeloproliferative
neoplasm (MPN), most commonly chronic myelomonocytic leukemia, The MDSs are a heterogeneous group of neoplasms, including refrac-
refractory anemia with excess blasts (RAEB), or the poorly understood tory cytopenia with unilineage dysplasia, RARS, refractory cytopenia
disorder of “atypical CML.” Some of the latter have JAK2 V617F mutations with multilineage dysplasia (RCMD), RAEB–1,2, MDS with isolated
and a phenotype consistent with chronic neutrophilic leukemia (Chaps. del(5q), MDS unclassifiable, and childhood MDS, including refractory
24
84 and 89). Cytogenetic analysis of marrow biopsies from these patients cytopenia of childhood (Chap. 87). Clonal chromosome abnormalities
commonly have a normal karyotype, +8, +13, del(20q), or i(17q). These can be detected in marrow cells of approximately 50 percent of patients
patients have a substantially shorter survival than do those whose cells with primary MDS at diagnosis (refractory anemia [RA], 25 percent;
have the t(9;22). Because each of the oral TKIs blocks kinase activities RARS, 10 percent; RCMD, 50 percent; RAEB –1,2, 50 to 70 percent;
in addition to BCR-ABL1, they have proven to be effective in other MDS with isolated del (5q), 100 percent) (see Table 13–2). 25,26 The pro-
disorders, including chronic MPNs with platelet-derived growth fac- portion varies with the risk that a subtype will transform to AML, which
tor receptor (PDGFR)-β rearrangements, a myeloproliferative variant is highest for RCMD and RAEB. The common chromosome changes,
of hypereosinophilic syndrome that expresses the FIP1L1-PDGFRA +8, del(5q), −7/del(7q), and del(20q), are similar to those seen in AML
fusion protein, and in patients with mast cell malignancies that express de novo. The recurring translocations that are closely associated with
an activating point mutation in KIT (Chap. 89). 18 the distinct morphologic subsets of AML de novo are almost never seen
in MDS. With the exception of MDS with isolated del(5q), the chromo-
some changes show no close association with the specific subtypes of
OTHER MYELOPROLIFERATIVE NEOPLASMS MDS. MDS with isolated del(5q) occurs in a subset of older patients,
A cytogenetically abnormal clone is present in 15 percent of untreated frequently women, with RA, generally low blast counts, and normal or
polycythemia vera patients compared with 40 percent of treated patients elevated platelet counts. These patients have an interstitial deletion of
27
(Table 13–2). When the disease transforms to acute myeloid leukemia 5q, typically as the sole abnormality, and can have a relatively benign
19
(AML), almost 100 percent have a cytogenetically abnormal clone. The course that extends over several years (Chap. 87). Diagnostic and
27
presence of a chromosome abnormality at diagnosis does not neces- prognostic information for the patients with a normal karyotype can be
sarily predict a short survival or the development of leukemia. How- provided by CMA, which can detect abnormalities in 10 to 15 percent
ever, a change in the karyotype may be an ominous sign. Marrow cells of these cases. Some abnormalities detectable by CMA, including sub-
frequently contain additional chromosomes (+8 or +9). Trisomy 8 and microscopic microdeletions in 4q24 affecting the TET2 gene, as well as
9 may occur together which is otherwise rare. Structural rearrange- LOH 7q, LOH 11q, and LOH 17p, were shown to be associated with a
19
ments most often involve a del(13q) or del(20q), noted in 30 percent of poor outcome in MDS. 28,29
patients. Loss of chromosome 7 (20 percent) and del(5q) (40 percent) Cytogenetic abnormalities in MDS are predictive of survival and
are often observed in the leukemic phase, and may be related to the progression to AML. Patients with a “very good outcome” have −Y
26
prior treatment received by these patients (Chap. 84). or del(11q) as the sole abnormality; those with a “good outcome” have

Kaushansky_chapter 13_p0173-0190.indd 178 17/09/15 6:32 pm