Page 434 - Clinical Hematology_ Theory _ Procedures ( PDFDrive )

418 PART 6 ■ Neoplastic Disorders

risk or ise se progression, respectively. Mut tions in these int ining the elic te ho eost sis between proli er -

genes re so ehow closely linke to the clinic l courses. tion n poptosis n pro otes cell surviv l by inhibiting

P tients whose leuke ic B cells express IgV h ve better cell e th. iRNAs re jor irect neg tive regul tors o
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surviv l r te (e.g., 24-ye r surviv l) co p re with p tients the Bcl2 nti poptotic protein n in irect ctiv tors o the

who l ck such ut tions (e.g., 6- to 8-ye r surviv l). intrinsic poptotic progr le ing to poptotic pepti se

T e leuke ic cells ro p tients with ew or no IgV ctiv ting ctor.
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ut tions ore requently h ve cytogenetic ch nges th t Myeloi cell leuke i -1 (Mcl-1) is n nti poptotic e -

orec st poor clinic l outco e (e.g., 11q22-23 eletion, ber o the Bcl2 protein ily. Incre se Mcl-1 expression is

17p eletion, triso y 12, or p53 ys unction). P tients with ssoci te with ilure to chieve re ission er tre t ent

biologic lly signif c nt nu bers o IgV ut tions ore re- with u r bine n chlor bucil in p tients with CLL.
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quently h ve chro oso l ch nges ssoci te with benign Mcl-1 expression y be use ul in pre icting poor response

course o the ise se (e.g., 13q14 eletion). to che oi unother py.

Note th t p tients with ly ph enop thy, spleno eg ly,
Zeta-Chain–Associated Protein 70 n p ncytopeni with n typic l ly phocyte popul tion

Another sign ling- ssoci te olecule, the zet -ch in– y h ve n cquire ut tion in gene th t is cruci l to cel-

ssoci te protein 70 (ZAP-70), w s recently iscovere to lul r poptosis. T e protein enco e by the FAS cell sur ce

be i erenti lly expresse in the CLL subgroup without IgV e th receptor gene (FAS) is e ber o the NF-receptor
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ut tion th t h poor outco es. ZAP-70, n enzy e nor- super ily. T is receptor cont ins e th o in th t h s

lly expresse in ly phocytes, is critic l or the ctiv - been shown to pl y centr l role in the physiologic l regul -

tion o cells by ntigen. T e expression o this -line ge tion o progr e cell e th. So tic ut tion o FAS h s

gene in CLL cells is surprising but h s been conf r e by been i plic te in the p thogenesis o v rious lign ncies

rese rch stu ies. In ppropri te expression o ZAP-70 in CLL n ise ses o the i une syste such s utoi une

y lter the ction o nother protein tyrosine kin se, Syk, ly phoproli er tive syn ro e (ALPS). ALPS is isor er o

oun in B ly phocytes. bnor l ly phocyte surviv l ue to ysregul tion o the

FAS poptotic p thw y.
Thym idine Kinase

Another new f n ing is the correl tion o the seru v lue Sel Suf ciency in Growth

o thy i ine kin se with IgVH gene ut tion l st tus n Sel -su ciency in growth e onstr tes th t nor l cells

lso with ise se progression. DNA icro rr y h s e - require growth sti uli co p re to c ncer cells th t re

onstr te th t CLL exhibits ch r cteristic gene expression c p ble o gener ting their own growth sign ls without h v-

prof le closely rel te to e ory B cells n in epen ent o ing to rely on itogens in the surroun ing environ ent in

the presence o IgVH ut tions. or er to ctively proli er te.

CD38 Stimulation o Angiogenesis and Dissemination

Expression o CD38, e br ne protein th t rks cellu- T is is ch r cteristic o the rrow n ly ph no es o

l r ctiv tion n tur tion n th t h s sign ling ctivity, p tients with CLL. P tients show high egree o tissue

o en correl tes with the presence o IgV ut tions. CD38 neov scul riz tion.
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sur ce expression on the lign nt cell is now viewe s n

in epen ent rker o p tient’s clinic l outco e. CD38+ Staging and Prognosis

B-CLL p tients re ch r cterize by ore v nce ise se CLL h s v ri ble clinic l course. Clinic l st ging syste s

st ge, lesser responsiveness to chemotherapy, n shorter (R i n Binet) or ssessing prognosis in CLL were evel-

surviv l ti es th n CD38-neg tive p tients. ope in the e rly 1980s, b se on e sily obt in ble biologic l

n clinic l p r eters.
MicroRNA Te st ging cl ssif c tion is

MicroRNA ( iRNA) expression prof les c n be use to istin-

guish nor l B cells ro lign nt B cells in CLL p tients. 0 Bone rrow n bloo ly phocytosis

A unique icroRNA sign ture is ssoci te with prognostic I Ly phocytosis with enl rge no es

ctors n ise se progression in CLL. Mut tions in iRNA II Ly phocytosis with enl rge spleen or liver or both

tr nscripts re co on n c n h ve unction l i port nce. III Ly phocytosis with ne i

iRNAs regul te the expression o protein-co ing genes IV Ly phocytosis with thro bocytopeni

n c n ct s oncogenes, tu or suppressors, or both. Most p tients with CLL now h ve R i st ge 0 or I ise se t

Alter tions in CLL ect the ollowing: i gnosis. P tients with e rly-st ge ise se re heterogeneous

group: pproxi tely 30% to 50% will h ve cceler te ise se
■ Ev sion o poptosis progression, n the re in er y live or ec es n pos-

■ Sel -su ciency in growth sibly never require ther py. Prognosis is roughly rel te to the

■ Sti ul tion o angiogenesis n isse in tion
extent o org n inf ltr tion t the ti e o i gnosis.

Ev sion o poptosis is ssoci te with overexpression At present, in ition to Binet st ges, the ut tion l st -

o the nti poptotic protein bcl2. BCL2 is responsible or tus o the V genes, olecul r rkers such s ZAP-70 n
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