Page 468 - Clinical Hematology_ Theory _ Procedures ( PDFDrive )

452 PART 6 ■ Neoplastic Disorders

Pathophysiology T e jority o Ph -positive p tients h ve the typic l
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t(9;22) tr nsl tions. T e reciproc l tr nsloc tion t(9;22) gen-
CML is clon l proli er tive isor er o the pluripotent er tes two novel usion genes: BCR-ABL on the eriv tive

he topoietic progenitor cell th t results in isor ere 22q-(Phil elphi ) chro oso e n ABL-BCR on chro-

proli er tion o cells. An excessive incre se in ostly ture oso e 9q+. T e ABL gene pro uct is protein tyrosine

yeloi cells in the peripher l bloo is the h ll rk o the kin se ( K), n the usion protein BCR-ABL h s constitu-

initi l (chronic) ph se o CML. T e isor erly exp nsion o tive kin se ctivity th t eregul tes sign l tr ns uction p th-

yeloi progenitor cells ppe rs to result ro lter tions in w ys, c using bnor l cell cycling, inhibition o poptosis,

their proli er tive c p city n shi in the b l nce between n incre se proli er tion o cells. Seventy-f ve to eighty

sel -renew l n i erenti tion, incre sing the nu ber o percent o p tients in bl st crisis o CML evelop other

progenitor cells n re ucing the pool o ste cells. Ste chro oso e berr tions in ition to the Ph chro o-
1
cells beco e p rt o the proli er ting co p rt ent, c us- so e. T e ost co on bnor lities re uplic tion

ing the neopl stic cell popul tion to exp n exponenti lly o the Ph chro oso e n triso y 8. Nonr n o clon l
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in l ter tur tion l co p rt ents, where they y lso be ch nges oun in 80% o p tients, in ition to triso y 8,

less responsive to growth regul tory sign ls ro cytokines inclu e +19 n loss o the Y chro oso e.

or the bone rrow icroenviron ent. In ition, e ec- T e t(9;22) tr nsloc tion c n lso be oun in 3% to 5% o

tive herence o i ture he topoietic CML progenitors chil ren n ults with cute yelogenous (FAB M1) leu-

to rrow stro l ele ents y cilit te their rele se into ke i n in bout 5% o chil ren n 10% to 25% o ults

the bloo . T e suppression o p thw ys o poptosis h s been with cute ly phobl stic (FAB L1 n L2 types) leuke i .

i plic te in the p thogenesis o CML.

CML is ch r cterize by chronic, in olent ise se course Genetic Alterations

th t requently tr ns or s into ter in l, cute bl st crisis

ph se. An cceler te ph se, when p tients beco e re r c- CML is the best-ch r cterize leuke i t olecul r

tive to tr ition l ther py, y prece e the cute ph se. level. P tients with CML n cute ly phobl stic leuke i

So e p tients y enter the ph se o bl st tr ns or tion express the BCR gene re rr nge ent (Fig. 23.2), which is the

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bruptly. olecul r counterp rt o the Ph chro oso e. T ese recip-
roc l tr nsloc tions involve the reloc tion n usion o the

Cytogenetics protooncogene c-ABL on the ist l r o chro oso e 9

to bre k in the newly i entif e genetic locus o chro o-
Te Ph chro oso e (Fig. 23.1), the f rst berr nt chro o- so e 22, known s BCR (bre kpoint cluster region). T e sig-
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so e escribe in lign nt isor er, w s iscusse by nif c nce o the presence o the Ph chro oso e is possibly
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Nowell n Hunger or in 1960. In 1973, it w s shown to rel te to plif c tion o the pro uct. T e BCR-ABL usion

result ro the reciproc l tr nsloc tion o DNA between gene is tr nscribe into chi eric RNA tr nscript, which

chro oso es 9 n 22. T e Ph chro oso e is the f rst is in turn tr nsl te into usion protein with bnor l
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e onstr ble he tologic l ch nge in ore th n 90% o structure n unction. T e BCR-ABL usion gene, RNA,

CML p tients n is present in yelogenous n erythroi n protein re i gnostic rkers o CML t the olecul r

precursors s well s eg k ryocytes. It is usu lly not oun level (Fig. 23.3).

in nor l ly phocytes. Evi ence o the role o mRNA tr nscripts s centr l e i-

tors o yeloi proli er tion n tr ns or tion in CML
ste s ro experi ents with o els o tu or evelop-

ent. T ese tr nscripts c use ctor-in epen ent n leu-
ke ogenic cell growth in he topoietic cell lines n c n
1–3 4–5
gener te in ice syn ro e th t closely rese bles hu n
CML. abl proteins re nonreceptor Ks th t h ve i port nt

6–12

13–15 16–18

19 20 21 22 X Y
FIGURE 23.2 Chronic yelogenous leuke i . T e Phil elphi
chro oso e er(22) is shown. (Reprinte ro Rubin R, Str yer

FIGURE 23.1 Phil elphi chro oso e. T is chro oso l ber- DS. Rubin’s Pathology: Clinicopathologic Foundations o Medicine,

r tion represents tr nsloc tion o the long r o chro oso e 22 5th e , Phil elphi , PA: Lippincott Willi s & Wilkins, 2008, with

to the long r o chro oso e 9. per ission.)