Page 1156 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 64 Pathobiology of Acute Lymphoblastic Leukemia 1015

glucocorticoid receptor by AKT. 374,375 In addition, both MYC and syndrome 323–325 and have been found to portend a poor prognosis in
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the PI3K-AKT pathway have been identified as key suppressors of adults ; however, more recent studies in the pediatric population
the proapoptotic factor BIM, which is required for mitochondrial suggest that CRLF2 may not be as poor a prognostic indicator as
apoptosis in normal T-cell development. 210,211,376,377 Taken together, originally thought, suggesting that in the absence of a Ph-like ALL
these findings thus suggest the potential clinical utility of PI3K-AKT expression profile, CRLF2 mutations are not an independent poor
pathway inhibitors in high-risk T-cell ALL, many of which are cur- prognostic indicator. 396,397
rently in human clinical trials. 378 A number of JAK2 inhibitors have been developed for the
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treatment of myeloproliferative syndromes, which generated
FLT3 in MLL-Rearranged Acute considerable excitement for the application of such inhibitors to
CRLF2/JAK2-mutant precursor B-cell ALL. However, one problem
Lymphoblastic Leukemia with first-generation (“type 1”) JAK2 inhibitors that stabilize JAK2
in its active conformation is that these drugs induce paradoxical
FLT3 encodes a receptor tyrosine kinase that is highly expressed in hyperactivation of JAK2, and these drugs have little therapeutic
399
early hematopoietic precursors, where it plays important functional activity in JAK2-mutant ALL. Paradoxical JAK2 phosphorylation
roles. 379,380 Multiple studies have shown that activating mutations of following treatment with type 1 JAK2 inhibitors is mediated by
FLT3, which lead to constitutive receptor tyrosine kinase activity even heterodimerization and trans-phosphorylation of JAK2 by other
400
in the absence of ligand, are common in leukemic myeloblasts in JAK family kinases, including JAK1 or TYK2. One promising
patients with AML but are rare in adults with ALL. 381–383 However, approach to overcome this obstacle is to target the chaperone protein
gene expression studies demonstrated high expression of FLT3 in HSP90, which binds and stabilizes both wild-type and mutant JAK2
most cases of ALL that involve MLL gene rearrangements or hyper- proteins. Indeed, treatment with small-molecule HSP90 inhibitors,
diploidy. 245,246,250 Additionally, activating mutations were identified in which are in human clinical trials, triggers JAK2 degradation and has
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18% of infants with MLL-rearranged ALL, in 21%–24% of promising activity in preclinical models. 399,401 An additional approach
hyperdiploid ALL cases, 251,384 and in all three cases of the prothymic has been the development of second-generation (“type 2”) JAK2
+
CD117/KIT subtype of T-cell ALL in adults examined. 385 inhibitors that stabilize JAK2 in its inactive conformation. One such
In the absence of FLT3 ligand, wild-type FLT3 receptors are type 2 JAK2 inhibitor has been shown to have significant activity
inactive because of autoinhibition mediated by the juxtamembrane as a single agent, and to synergize with dexamethasone, both in
402
domain of the receptor. Upon binding of FLT3 ligand, normal FLT3 vitro and in vivo in preclinical models of ALL. These findings
receptors homodimerize, become activated by phosphorylation, and support the need for human clinical trials testing this approach
lead to the activation of signal-transduction pathways that promote in patients with CRLF2-rearranged or JAK2-mutant precursor
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proliferation and cell survival. Activating mutations of FLT3 found B-cell ALL.
in leukemias occur in two separate regions of the gene. In-frame
tandem duplications in the juxtamembrane domain lead to loss of
the autoinhibition mediated by this domain, with subsequent dimer- Interleukin-7 Receptor Mutations in T-Cell Acute
387
ization and receptor activation in the absence of FLT3 ligand. Lymphoblastic Leukemia
Alternatively, point mutations or insertions in the second tyrosine
kinase domain of the FLT3 receptor lead to autophosphorylation and IL7R is required for normal T-cell development, with loss-of-function
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activation of downstream signaling in the absence of FLT3 IL7R mutations leading to severe combined immunodeficiency.
ligand. 383,388,389 Small-molecule inhibitors of the FLT3 kinase lead to The IL-7R protein can heterodimerize with either IL2Rγ, resulting
apoptosis in AML cell lines in vitro. A phase I study of the FLT3 in the receptor for IL-7, or with CRLF2 to form the receptor for
inhibitor, quizartinib, demonstrated an acceptable toxicity profile and TSLP. 403,404 Recently, point mutations in the IL-7R have been
is currently being investigated in phase II trials, both as monotherapy described in approximately 10% of T-cell ALL cases. 40,405,406 These
and in combination with chemotherapy or BMT in adults with AML point mutations typically introduce a novel cysteine residue in the
and MDS. 390,391 These small-molecule inhibitors are also active transmembrane domain of the protein that permits formation of a
against MLL-rearranged ALL cell lines, 250,392 and hold promise as neomorphic disulfide bond between mutant IL-7R homodimers.
targeted therapies for cases of ALL that rely on aberrant activation of This leads to ligand-independent receptor dimerization and activa-
FLT3. tion of downstream oncogenic signal transduction pathways, includ-
ing JAK–STAT and PI3K–AKT. A potential therapeutic strategy to
CRLF2 and JAK2 Mutations in Precursor B-Cell target oncogenic activation of mutant IL-7R proteins is the reduction
of the neomorphic disulfide bond. Indeed, N-acetylcysteine, a reduc-
Acute Lymphoblastic Leukemia ing agent developed clinically for the treatment of acetaminophen
overdose, has been shown to reduce the extracellular cysteine bond
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The CRLF2 cytokine receptor binds its ligand, thymic stromal and inhibit signaling by mutant IL-7R proteins. Clinical trials
lymphopoietin (TSLP), as a heterodimeric complex with the IL-7 testing this approach are under development.
receptor subunit (IL-7R). TSLP-CRLF signaling plays physiologic
roles during normal B-cell development and in inflammation.
Genomic analyses of precursor B-cell ALL patient samples revealed Tumor Suppressor Gene Inactivation
recurrent deletions within the pseudoautosomal region of Xp22.3/
Yp11.3 that result in overexpression of the entire coding region of Much attention has been focused on tumor suppressors, whose loss
CRLF2 under the control of gene regulatory elements of P2RY8, a of function via deletion or mutational inactivation leads to malignant
purinergic receptor that is expressed at high levels in ALL cells. 393–395 transformation. Knudson first proposed that inactivation of both
In some cases, such rearrangements are also accompanied by a Phe- alleles of a single locus is needed to initiate the development of reti-
232Cys point mutation in CRLF2 that promotes constitutive noblastoma, basing his hypothesis on the observed frequencies of
408
dimerization and cytokine-independent growth. 394,395 Interestingly, hereditary and sporadic forms of this disease. Allelic loss of defined
aberrant CRLF2 expression very frequently co-occurs with JAK2- regions of many different chromosomes has been linked to specific
activating mutations, and these two genetic lesions collaborate types of human tumors. By analogy with the findings in retinoblas-
to induce ligand-independent activation of downstream signal trans- toma, a reasonable hypothesis is that each of these regions harbors a
duction pathways, suggesting that CRLF2 may act as a scaffold that tumor suppressor gene whose product is uniquely involved in the
is required for activation of oncogenic JAK-STAT signaling by JAK2 inhibition of cell cycle progression and promotion of terminal dif-
mutations in precursor B-cell ALL. 393–395 Overall, CRLF2 rearrange- ferentiation of the normal cells that give rise to these different types
ments occur with especially high frequency in patients with Down of tumors.